Compounds and compositions as protein kinase inhibitors

ABSTRACT

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases and disorders associated with kinase activity, particularly diseases associated with the activity of CDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ, Src, Mek1 and CK1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 60/467,738 (filed May 1, 2003). The fulldisclosure of this application is incorporated herein by reference inits entirety and for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent diseases and disorders associated withkinase activity, particularly diseases associated with the activity ofCDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ, Mek1, CK1,c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1 and c-Met kinases.

2. Background

Kinases are involved in many aspects of cellular metabolism,proliferation, differentiation and development. A partial, non-limitinglist of kinases include CDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3,c-Kit, PDGFRβ, Mek1, CK1, c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1and c-Met kinases. Many diseases are associated with abnormal cellularresponses triggered by protein kinase-mediated events. Disease areasinclude autoimmune diseases, inflammatory diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand hormone-related diseases. In particular, kinases have beenimplicated in various diseases including: diabetes; Alzheimer's diseaseand mood disorders such as bipolar disorder; CNS disorders such asmanic-depressive disorder and neurodegenerative diseases; cardiomyocetehypertrophy; and development and regulation of sperm motility. Further,kinases been implicated in hair loss, schizophrenia and neurotrauma, forexample, stroke, traumatic brain surgery and spinal cord trauma. Thesediseases may be caused by, or result in, the abnormal operation ofcertain cell signaling pathways, for example, those signaling pathwaysin which CDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ,Mek1, CK1, c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1 and c-Metkinases play a role. Accordingly, molecules that modulate the activityof kinase-mediated signaling are useful as therapeutic agents in thetreatment of such diseases.

SUMMARY OF THE INVENTION

In one aspect, this invention provides compounds of Formula I:

in which:

-   -   R¹ and R² are independently selected from hydrogen, halo, cyano,        nitro, amino, phenyl, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; or    -   R¹ and R² taken together with the carbon atoms to which R¹ and        R² are attached form a phenyl ring optionally substituted by 1        to 3 substituents selected from halo, cyano, nitro, amino,        methanesulfonyl, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;    -   R³, R⁴ and R⁵ are independently selected from hydrogen,        C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and        halo-substituted-C₁₋₆alkoxy; and    -   —X—Y— is selected from —CHZ-CH₂—, —C(=Z)CH₂— and —CZ=CH—;        wherein =Z is selected from formula (a) and (b) and -Z is        selected from formula (c),(d) and (e):        wherein R⁶, R⁸ and R⁹ are independently selected from hydrogen,        C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and        halo-substituted-C₁₋₆alkoxy;    -   R⁷ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,        —C(O)OR¹¹ and —C(O)R¹¹; wherein R¹¹ is hydrogen or C₁₋₆alkyl;    -   R¹⁰ is selected from C₁₋₆alkyl, —NR¹¹R¹², C₆₋₁₀aryl-C₀₋₄alkyl,        C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl and        C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any alkyl is optionally        substituted with —NR¹¹R¹¹, C₁₋₆alkoxy or hydroxy; and wherein        any cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        optionally substituted by 1 to 3 substituents selected from        halo, hydroxy, cyano, amino, nitro, —C(O)OR¹¹, —C(O)NR¹¹R¹¹,        —SNR¹¹R¹¹, —S(O)NR¹¹R¹¹, —S(O)₂NR¹¹R¹¹, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;        wherein R¹¹ is hydrogen or C₁₋₆alkyl; R¹² is C₃₋₁₂cycloalkyl        optionally substituted with amino; or    -   R⁹ and R¹⁰ together with the nitrogen to which R⁹ and R¹⁰ are        attached form C₃₋₁₀heterocycloalkyl; and the N-oxide        derivatives, prodrug derivatives, protected derivatives,        individual isomers and mixtures of isomers thereof; and the        pharmaceutically acceptable salts and solvates (e.g. hydrates)        of such compounds.

In a second aspect, this invention provides a pharmaceutical compositionwhich contains a compound of Formula I or an N-oxide derivative,individual isomer or mixture of isomers thereof, or a pharmaceuticallyacceptable salt thereof, in admixture with one or more suitableexcipients.

In a third aspect, this invention provides a method for treating adisease in an animal in which inhibition of CDK1, CDK2, CDK4, CDK5,GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ, Mek1, CK1, c-Ab1, KDR, IGF-1R,Flt-1, Tek, c-src, FGFR-1 and/or c-Met kinases activity can prevent,inhibit or ameliorate the pathology and/or symptomology of the disease,which method comprises administering to the animal a therapeuticallyeffective amount of a compound of Formula I or a N-oxide derivative,individual isomer or mixture of isomers thereof; or a pharmaceuticallyacceptable salt thereof.

In a fourth aspect, this invention provides the use of a compound ofFormula I in the manufacture of a medicament for treating a disease inan animal in which CDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit,PDGFRβ, Mek1, CK1, c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1 and/orc-Met kinases activity contributes to the pathology and/or symptomologyof the disease.

In a fifth aspect, this invention provides a process for preparingcompounds of Formula I and the N-oxide derivatives, prodrug derivatives,protected derivatives, individual isomers and mixtures of isomersthereof; and the pharmaceutically acceptable salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds that are useful in the treatment and/orprevention of diseases or disorders mediated by kinase activity. Alsoprovided are methods for treating such diseases or disorders.

Definitions

In this specification, unless otherwise defined:

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl, alkoxy, acyl, alkylthio, alkylsulfonyland alkylsulfinyl, can be either straight-chained or branched. “Alkenyl”as a group and as a structural element of other groups contains one ormore carbon-carbon double bonds, and can be either straight-chain, orbranched. Any double bonds can be in the cis- or trans-configuration. Apreferred alkenyl group is vinyl. “Alkynyl” as a group and as structuralelement of other groups and compounds contains at least one C≡C triplebond and can also contain one or more C═C double bonds, and can, so faras possible, be either straight-chain or branched. A preferred alkynylgroup is propargyl. Any cycloalkyl group, alone or as a structuralelement of other groups can contain from 3 to 8 carbon atoms, preferablyfrom 3 to 6 carbon atoms.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl can be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group. For example, arylene as used in thisapplication can be phenylene or naphthylene.

“Halo” or “halogen” means F, Cl, Br or I, preferably F or Cl.Halo-substituted alkyl groups and compounds can be partially halogenatedor perhalogenated, whereby in the case of multiple halogenation, thehalogen substituents can be identical or different. A preferredperhalogenated alkyl group is for example trifluoromethyl.

“Heteroaryl” means aryl, as defined in this application, provided thatone or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from N, O or S, and each ring is comprised of 5 to6 ring atoms, unless otherwise stated. For example, heteroaryl as usedin this application includes thiazolyl, thiophenyl, quinolinyl,pyrimidinyl, pyrazolyl, pyridinyl, furanyl, isoxazolyl, benzoxazolyl orbenzo[1,3]dioxolyl, preferably pyrimidinyl, quinolinyl or pyridinyl.“Heteroarylene” means heteroaryl, as defined in this application,provided that the ring assembly comprises a divalent radical.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds that are useful for treating orpreventing diseases or disorders that are mediated by kinase activity.

In some embodiments compounds of the invention are of Formula Ia:

in which R¹ and R² are independently selected from hydrogen and halo; orR¹ and R² taken together with the carbon atoms to which R¹ and R² areattached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo, methanesulfonyl, nitro and amino; R³,R⁴, R⁵, R⁶, R⁸ and R⁹ are independently selected from hydrogen andC₁₋₆alkyl; and R⁷ is selected from hydrogen, C₁₋₆alkyl and —C(O)R¹¹;wherein R¹¹ is hydrogen or C₁₋₆alkyl.

In a further embodiment, in relation to compounds of formula Ia, R¹ andR² are independently selected from hydrogen and halo; R³, R⁴, R⁵, R⁶, R⁸and R⁹ are hydrogen; and R⁷ is selected from hydrogen, ethyl and—C(O)CH₃.

Preferred compounds of formula Ia are:4-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;N-[5-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-4-oxo-4,5-dihydro-1H-imidazol-2-yl]-acetamide;2,3-dibromo-4-(2-ethylamino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;and4-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dibromo-6-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;

In another embodiment, in relation to compounds of formula Ia, R¹ and R²taken together with the carbon atoms to which R¹ and R² are attachedform a phenyl ring optionally substituted by 1 to 3 substituentsselected from halo, methanesulfonyl, nitro and amino; R³, R⁴, R⁶, R⁸ andR⁹ are hydrogen; R⁵ is C₁₋₆alkyl; and R⁷ is selected from hydrogen and—C(O)R¹¹; wherein R¹¹ is C₁₋₆alkyl. Preferably, R⁵ is methyl and R⁷ ishydrogen or —C(O)CH₃.

Further preferred compounds of formula Ia are:5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-bromo-3,4,5,10-tetrahydro-2H-azepino [3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-chloro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-fluoro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-9-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-dihydro-imidazol-4-ylidene)-7-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-amino-5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5, 10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-Amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-methanesulfonyl-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;9-amino-5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;N-[5-(7-bromo-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-4-oxo-4,5-dihydro-1H-imidazol-2-yl]-acetamide;and5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-bromo-3-methyl-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.

In another embodiment, compounds of the invention are of Formula Ib:

in which R¹ and R² are independently selected from hydrogen, halo andphenyl; or R¹ and R² taken together with the carbon atoms to which R¹and R² are attached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo and amino; R³, R⁴ and R⁵ areindependently selected from hydrogen and C₁₋₆alkyl; R⁹ is hydrogen; andR¹⁰ is selected from C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl andC₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any aryl or heteroaryl is optionallysubstituted by 1 to 3 substituents selected from halo, nitro, —C(O)OH,—S(O)₂NH₂, C₁₋₆alkoxy and halo-substituted-C₁₋₆alkyl.

In a further embodiment, R¹ and R² are independently selected from haloand phenyl; R³ and R⁴ are hydrogen and R⁵ is methyl; R⁹ is hydrogen; R¹⁰is selected from C₆₋₁₀aryl-C₀₋₄alkyl and C₅₋₁₀heteroaryl-C₀₋₄alkyl;wherein any aryl or heteroaryl is optionally substituted by halo, nitro,—C(O)OH and halo-substituted-C₁₋₆alkyl.

Preferred compounds of formula Ib are:2-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoicacid;4-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoicacid;2,3-dibromo-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-[(4-nitro-phenyl)-hydrazono]-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;4-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzenesulfonamide;2,3-dibromo-4-[(7-chloro-quinolin-4-yl)-hydrazono]-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-[(5-trifluoromethyl-pyrimidin-2-yl)-hydrazono]-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-(pyridin-3-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-(pyridin-4-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2-phenyl-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;6-methyl-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;and2,3-dichloro-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one.

In yet a further embodiment, R¹ and R² taken together with the carbonatoms to which R¹ and R² are attached form a phenyl ring optionallysubstituted by 1 to 3 substituents selected from halo and amino; R³, R⁴and R⁵ are independently selected from hydrogen and C₁₋₆alkyl; R⁹ ishydrogen; and R¹⁰ is selected from C₆₋₁₀aryl-C₀₋₄alkyl andC₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any aryl or heteroaryl is optionallysubstituted by 1 to 3 substituents selected from halo, nitro, —C(O)OH,—S(O)₂NH₂, C₁₋₆alkoxy and halo-substituted-C₁₋₆alkyl.

Further preferred compounds of formula Ib are:5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-bromo-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;9-amino-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;4-[N-(7-chloro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-benzenesulfonamide;7-chloro-5-(pyridin-4-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-(pyridin-3-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-fluoro-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-bromo-3-methyl-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;4-[N-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-benzenesulfonamide;7-fluoro-5-(pyridin-3-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-fluoro-5-[(6-methoxy-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(6-methoxy-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-[(2-chloro-pyridin-3-yl)-hydrazono]-7-fluoro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(2-chloro-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(5-chloro-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-[(5-chloro-pyridin-2-yl)-hydrazono]-7-fluoro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;6-[N′-(7-chloro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-pyridine-3-sulfonicacid amide;6-[N′-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-pyridine-3-sulfonicacid amide;7-fluoro-5-[(5-trifluoromethyl-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(5-trifluoromethyl-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(5-nitro-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;and7-chloro-5-[(6-chloro-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.

In a further embodiment, compounds of the invention are selected fromFormula Ic₁ and Ic₂:

in which R¹ and R² taken together with the carbon atoms to which R¹ andR² are attached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo, cyano, nitro, amino, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;R³, R⁴ and R⁵ are hydrogen; R⁹ is selected from hydrogen and C₁₋₆alkyl;and R¹⁰ is selected from C₁₋₆alkyl, —NR¹¹R¹², C₆₋₁₀aryl-C₀₋₄alkyl andC₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any alkyl is optionally substitutedwith —NR¹¹R¹¹, C₁₋₆alkoxy or hydroxy; and wherein any aryl or heteroarylis optionally substituted by 1 to 3 substituents selected from halo,—C(O)NR¹¹R¹¹ and —S(O)₂NR¹¹R¹¹; wherein R¹¹ is hydrogen or C₁₋₆alkyl;R¹² is C₃₋₁₂cycloalkyl optionally substituted with amino; or R⁹ and R¹⁰together with the nitrogen to which R⁹ and R¹⁰ are attached formC₃₋₁₀heterocycloalkyl.

In a further embodiment, R¹ and R² taken together with the carbon atomsto which R¹ and R² are attached form a phenyl ring optionallysubstituted by 1 to 3 halo substituents; R⁹ is hydrogen or methyl; andR¹⁰ is selected from methyl, ethyl, propyl, pyridinyl, pyridinyl-methyl,2-amino-ethyl, 2-hydroxyethyl, 2-amino-propyl, 2-dimethylamino-ethyl,2-methoxy-ethyl; and wherein any heteroaryl is optionally substituted by1 to 3 substituents selected from halo, —C(O)NH₂ and —S(O)₂NH₂; or R⁹and R¹⁰ together with the nitrogen to which R⁹ and R¹⁰ are attached formmorpholino or piperazinyl.

Preferred compounds of formula Ic are:2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-pyridin-3-yl-acetamide;2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-pyridin-4-yl-acetamide;4-[2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetylamino]-benzamide;2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(4-sulfamoyl-phenyl)-acetamide;2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(3-sulfamoyl-phenyl)-acetamide;2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-sulfamoyl-phenyl)-acetamide;N-(2-amino-cyclohexyl)-2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(4-amino-cyclohexyl)-2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(4-hydroxy-cyclohexyl)-2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-pyridin-4-ylmethyl-acetamide;N-(2-chloro-pyridin-3-yl)-2-(1-oxo-1,2,3,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(6-chloro-pyridin-3-yl)-2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(6-chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;N-(2-chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(3-sulfamoyl-phenyl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-4-ylmethyl-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-4-yl-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-propyl-acetamide;N-(2-amino-ethyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(2-hydroxy-ethyl)-acetamide;N-(3-amino-propyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;N-(2-dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(2-methoxy-ethyl)-N-methyl-acetamide;7-fluoro-5-(2-morpholin-4-yl-2-oxo-ethyl)-3,10-dihydro-2H-azepino[3,4-b]indol-1-one;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(2-sulfamoyl-phenyl)-acetamide;7-fluoro-5-(2-oxo-2-piperazin-1-yl-ethyl)-3,10-dihydro-2H-azepino[3,4-b]indol-1-one;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(4-sulfamoyl-phenyl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-2-yl-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-3-yl-acetamide;4-[2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetylamino]-benzamide;N-(2-Amino-cyclohexyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;N-(2-Dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(3-hydroxy-propyl)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-hydroxy-ethyl)-acetamide;N-(2-Amino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-pyridin-3-yl-ethyl)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-pyridin-2-yl-ethyl)-acetamide;N-(4-Amino-cyclohexyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(2-Amino-cyclohexyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;and7-Fluoro-5-(2-oxo-2-piperazin-1-yl-ethylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.

In a further embodiment, compounds of the invention are of Formula Id:

in which R¹ and R² are independently halo; or R¹ and R² taken togetherwith the carbon atoms to which R¹ and R² are attached form a phenyl ringoptionally substituted by 1 to 3 substituents selected from halo andnitro; R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; and R⁷ is hydrogen orC₁₋₆alkyl.

Preferred compounds of formula Id are:2,3-dibromo-4-(2-ethylamino-3H-imidazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;5-(2-amino-3H-imidazol-4-yl)-7-bromo-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-3H-imidazol-4-yl)-7-chloro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;and5-(2-amino-3H-imidazol-4-yl)-9-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.

In a further embodiment, compounds of the invention are of Formula Ie:

in which R¹ and R² taken together with the carbon atoms to which R¹ andR² are attached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo, cyano, nitro, amino, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;R³, R⁴ and R⁵ are hydrogen; R⁹ is selected from hydrogen and C₁₋₆alkyl;and R¹⁰ is selected from C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl andC₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any alkyl is optionally substitutedwith —NR¹¹R¹¹, C₁₋₆alkoxy or hydroxy; and wherein any aryl or heteroarylis optionally substituted by 1 to 3 substituents selected from halo,—C(O)NR¹¹R¹¹ and —S(O)₂NR¹¹R¹¹; wherein R¹¹ is hydrogen or C₁₋₆alkyl; orR⁹ and R¹⁰ together with the nitrogen to which R⁹ and R¹⁰ are attachedform C₃₋₁₀heterocycloalkyl.

In a further embodiment, R¹ and R² taken together with the carbon atomsto which R¹ and R² are attached form a phenyl ring optionallysubstituted by 1 to 3 halo substituents; R⁹ is hydrogen or methyl; andR¹⁰ is selected from methyl, ethyl, propyl, pyridinyl, pyridinyl-methyl,2-amino-ethyl, 2-hydroxyethyl, 2-amino-propyl, 2-dimethylamino-ethyl,2-methoxy-ethyl; and wherein any heteroaryl is optionally substituted by1 to 3 substituents selected from halo, —C(O)NH₂ and —S(O)₂NH₂; or R⁹and R¹⁰ together with the nitrogen to which R⁹ and R¹⁰ are attached formmorpholino or piperazinyl. Preferred compounds of formula Ie are:1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-3-yl-urea;4-[3-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-ureido]-benzenesulfonamide;3-[3-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-ureido]-benzenesulfonamide;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-propyl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-4-yl-urea;1-(2-Chloro-pyridin-4-yl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-2-yl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-isoxazol-3-yl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-thiazol-2-yl-urea;1-(4-Amino-cyclohexyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(3-hydroxy-propyl)-urea;1-(2-Dimethylamino-ethyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(2-hydroxy-ethyl)-urea;1-(2-Amino-ethyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-4-ylmethyl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(2-pyridin-3-yl-ethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(2-pyridin-2-yl-ethyl)-urea;and1-(2-Amino-cyclohexyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea.

The invention provides forms of the compound that have the hydroxyl oramine group present in a protected form; these function as prodrugs.Prodrugs are compounds that are converted into an active drug form afteradministration, through one or more chemical or biochemicaltransformations. Forms of the compounds of the present invention thatare readily converted into the claimed compound under physiologicalconditions are prodrugs of the claimed compounds and are within thescope of the present invention. Examples of prodrugs include forms wherea hydroxyl group is acylated to form a relatively labile ester such asan acetate ester, and forms where an amine group is acylated with thecarboxylate group of glycine or an L-amino acid such as serine, formingan amide bond that is particularly susceptible to hydrolysis by commonmetabolic enzymes. The present invention also includes both theenzymatically phosphorylated or dephosphorylated compounds of Formula I,optionally in equilibrium.

Compounds of Formula I can exist in free form or in salt form, e.g.addition salts with inorganic or organic acids, e.g. an ammonium salt orsalts with metals such as lithium, sodium, potassium, calcium, zinc ormagnesium, or a mixture thereof. Compounds of Formula I and their saltsin hydrate or solvate form are also part of the invention.

When the compounds of Formula I have asymmetric centers in the molecule,various optical isomers are obtained. The present invention alsoencompasses enantiomers, racemates, diastereoisomers and mixturesthereof. Moreover, when the compounds of Formula I include geometricisomers, the present invention embraces cis-compounds, trans-compoundsand mixtures thereof. Similar considerations apply in relation tostarting materials exhibiting asymmetric carbon atoms or unsaturatedbonds as mentioned above.

Methods for Preparing Kinase Inhibitors

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be -used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula Ia and Id can be prepared by proceeding as in thefollowing Reaction scheme 1:

in which R¹, R², R³, R⁵, R⁶, R⁷ and R⁸ are as defined for Formula Iabove.

Compounds of Formula Id can be prepared by reacting a compound offormula 2 with a compound of formula 3. The reaction can be effected inthe presence of methanesulfonic acid at a temperature of 45 to 50° C.and requires 1 to 24 hours to complete. Compounds of Formula Ia can beprepared from compounds of Formula Id by reacting with Br₂ and NaOAc inacetic acid.

Compounds of Formula Ib can be prepared by proceeding as in thefollowing Reaction scheme 2:

in which R¹, R², R³, R⁵, R⁹ and R¹⁰ are as defined for Formula I above.

Compounds of Formula Ib can be prepared by reacting a compound offormula 4 with a compound of formula 5. The reaction can be effected inthe presence of a suitable acid (e.g. HCl, and the like), a suitablealcohol (e.g., ethanol, and the like) at a temperature of 80 to 90° C.and requires 1 to 5 hours to complete.

Compounds of Formula Ic can be prepared by proceeding as in thefollowing Reaction scheme 3:

in which R¹, R², R³, R⁵, R⁹ and R¹⁰ are as defined for Formula I above.

Compounds of Formula Ic₁ can be prepared by reacting a compound offormula 6 with a compound of formula 8. The reaction can be effected inthe presence of HATU, a suitable solvent (e.g., DMF, and the like) at atemperature of 15 to 20° C. and requires 0.5 to 2 hours to complete. Acompound of formula 7 can be prepared by reacting a compound of formula6 with diphenylphosphoryl azide. The reaction can be effected in thepresence of triethylamine, a suitable solvent (e.g., DMF, and the like)at a temperature of 15 to 20° C. and requires 0.5 to 12 hours tocomplete. Compounds of Formula Ic₂ can be prepared by reacting acompound of formula 7 with a compound of formula 8. The reaction can beeffected in a suitable solvent (e.g., toluene, and the like) at atemperature of 100 to 120° C. and requires 0.5 to 2 hours to complete.

Additional Processes for Preparing Compounds of the Invention:

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventioncan be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T W. Greene, “Protecting Groupsin Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc., 1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferable, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

-   -   (a) reacting a compound of formula 2 with formula 3; reacting a        compound of formula 4 with formula 5, reacting a compound of        formula 6 with formula 7; or converting a compound of formula Id        to formula Ia; and for each of these:    -   (b) optionally converting a compound of the invention into a        pharmaceutically acceptable salt;    -   (c) optionally converting a salt form of a compound of the        invention to a non-salt form;    -   (d) optionally converting an unoxidized form of a compound of        the invention into a pharmaceutically acceptable N-oxide;    -   (e) optionally converting an N-oxide form of a compound of the        invention to its unoxidized form;    -   (f) optionally resolving an individual isomer of a compound of        the invention from a mixture of isomers;    -   (g) optionally converting a non-derivatized compound of the        invention into a pharmaceutically acceptable prodrug derivative;        and    -   (h) optionally converting a prodrug derivative of a compound of        the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

Methods and Pharmaceutical Compositions for Treating CDK RelatedConditions

The compounds of Formula I in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, forexample, as indicated by the in vitro tests of Example 8 and aretherefore indicated for therapy of diseases and disorders associatedwith altered CDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit,PDGFRβ, Mek1, CK1, c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1 andc-Met activity. A 10 μM concentration of a compound of Formula Ipreferable inhibits activity of one or more kinases selected from CDK1,CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ, Mek1, CK1,c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1 and c-Met by more than 70%(For examples, see Table 2). Further, compounds of Formula I preferablyshow an IC₅₀ against one or more of CDK5, CDK1 and GSK3β kinases in therange of 1×10⁻⁹ to 1×10⁻⁵ M, preferably less than 500 nM, morepreferably less than 250 nM.

This invention also provides a method for preventing or treatingdiseases or conditions comprising abnormal cell growth in a mammal,including a human, comprising administering to the mammal a compound ofFormula I in an amount effective to inhibit CDK1, CDK2, CDK4, CDK5,GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ, Mek1, CK1, c-Ab1, KDR, IGF-1R,Flt-1, Tek, c-src, FGFR-1 and c-Met kinase activity. Such diseases orconditions include, for example, cancer. The cancer may be a carcinoma,for example carcinoma of the bladder, breast, colon, kidney, liver,lung, for example small cell lung cancer, esophagus, gall bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, or skin, forexample squamous cell carcinoma; a hematopoietic tumor of lymphoidlineage, for example leukemia, acute lymphocytic leukemia, B-celllymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor ofmyeloid lineage, for example acute and chronic myelogenous leukemias,myelodyplastic syndrome, or promyelocytic leukemia; a tumor ofmesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; atumor of the central or peripheral nervous system, for exampleastrocytoma, neuroblastomas, glioma or schwannoma; melanoma; seminoma;teratocarcinoma; osteosarcoma; xenoderoma pigmentoum; keratoctanthoma;thyroid follicular cancer; or Kaposi's sarcoma. Diseases or conditionscomprising benign abnormal cell growth include benign prostatehyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,atherosclerosis, pulmonary fibrosis, arthritis, psoriasis,glomerulonephritis, restenosis, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, fungal infection,and endotoxic shock.

This invention also provides a method for treating a neurodegenerativedisease or condition in a mammal, including a human, comprisingadministering to the mammal a compound of formula 1 in an amounteffective in treating said disease or condition. Such neurodegenerativediseases or conditions include, for example, Huntington's disease,stroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, epilepsy, amyotrophic lateral sclerosis, pain, viral induceddementia for example AIDS induced dementia, neurodegeneration associatedwith bacterial infection, migraine, hypoglycemia, urinary incontinence,brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementiaof the Alzheimer's type, mild cognitive impairment, age-relatedcognitive decline, emesis, corticobasal degeneration, dementiapugilistica, Down's syndrome, myotonic dystrophy, Niemann-Pick disease,Pick's disease, prion disease with tangles, progressive supranuclearpalsy, lower lateral sclerosis, and subacute sclerosingpanencephalistis.

This invention also provides a method for treating a disease orcondition the treatment of which can be effected or facilitated byaltering dopamine mediated neurotransmission in a mammal, including ahuman, comprising administering to the mammal a compound of formula 1 inan amount effective in treating said disease or condition. Such diseasesor conditions include, for example, Parkinson's disease; schizophrenia;schizophreniform disorder; schizoaffective disorder, for example of thedelusional type or the depressive type; delusional disorder;substance-induced psychotic disorder, for example psychosis induced byalcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,opioids, or phencyclidine; personality disorder of the paranoid type;personality disorder of the schizoid type; drug addiction, includingnarcotic (e.g. heroin, opium, and morphine), cocaine and alcoholaddiction; drug withdrawal, including narcotic, cocaine and alcoholwithdrawal ; obsessive compulsive disorder; Tourette's syndrome;depression; a major depressive episode, a manic or mixed mood episode, ahypomanic mood episode, a depressive episode with atypical features orwith melancholic features or catatonic features, a mood episode withpostpartum onset; post-stroke depression, major depressive disorder,dysthymic disorder, minor depressive disorder, premenstrual dysphoricdisorder, post-psychotic depressive disorder of schizophrenia, a majordepressive disorder superimposed on a psychotic disorder such asdelusional disorder or schizophrenia, a bipolar disorder, for examplebipolar I disorder, bipolar II disorder, cyclothymic disorder; anxiety;attention deficit and hyperactivity disorder; and attention deficitdisorder.

The required dosage will of course vary depending on the mode ofadministration, the particular condition to be treated and the effectdesired. In general, satisfactory results are indicated to be obtainedsystemically at daily dosages of from about 0.03 to 2.5 mg/kg per bodyweight. An indicated daily dosage in the larger mammal, e.g. humans, isin the range from about 0.5 mg to about 100 mg, convenientlyadministered, for example, in divided doses up to four times a day or inretard form. Suitable unit dosage forms for oral administration comprisefrom ca. 1 to 50 mg active ingredient.

The compounds of Formula I can be administered by any conventionalroute, in particular enterally, for example, orally, e.g. in the form oftablets or capsules, or parenterally, for example, in the form ofinjectable solutions or suspensions, topically, e.g. in the form oflotions, gels, ointments or creams, or in a nasal or a suppository form.Pharmaceutical compositions comprising a compound of Formula I in freeform or in pharmaceutically acceptable salt form in association with atleast one pharmaceutical acceptable carrier or diluent can bemanufactured in conventional manner by mixing with a pharmaceuticallyacceptable carrier or diluent.

The compounds of Formula I can be administered in free form or inpharmaceutically acceptable salt form, for example, as indicated above.Such salts can be prepared in a conventional manner and exhibit the sameorder of activity as the free compounds.

Also provided by the invention are compounds of Formula I, in free formor in a pharmaceutically acceptable salt form for use in treatment ofconditions such as those described above. Pharmaceutical compositions,that includes a compound of Formula I in free form or pharmaceuticallyacceptable salt form, in association with a pharmaceutically acceptablediluent or carrier thereof are also provided by the invention.

Also provided by the invention are methods involving co-administration,e.g. concomitantly or in sequence, of a therapeutically effectivenon-toxic amount of a compound of Formula I and at least a second drugsubstance. For example, the compounds of Formula I can be administeredas the sole active ingredient or in conjunction with, e.g. as anadjuvant to, other drugs e.g. a COX-II inhibitor, an anti-depressant oranxiolytic compound, a NK-1 receptor antagonist, a 5HT_(1D) receptorantagonist, a SSRI, an antipsychotic compound, an acetyl cholinesteraseinhibitor, a tissue plasminogen activator, a neutrophil inhibitoryfactor, a NMDA receptor antagonist or a potassium channel modulator.

Where the compounds of Formula I are administered in conjunction withother therapies, dosages of the co-administered compounds will of coursevary depending on the type of co-drug employed, on the specific drugemployed, on the condition being treated and so forth.

Also provided by the invention are pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of Formula I asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent, e.g. a COX-II inhibitor, ananti-depressant or anxiolytic compound, a NK-1 receptor antagonist, a5HT_(1D) receptor antagonist, a SSRI, an antipsychotic compound, anacetyl cholinesterase inhibitor, a tissue plasminogen activator, aneutrophil inhibitory factor, a NMDA receptor antagonist or a potassiumchannel modulator. The kit can comprise instructions for itsadministration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

EXAMPLES

The present invention is further exemplified, but not limited by, thefollowing examples that illustrate the preparation of compounds offormula I (examples), and their intermediates (References), according tothe invention.

Reference 12,3-Dibromo-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one

To a solution of 3-[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-propionicacid ethyl ester (7.80 g, 21.1 mmol) in 160 mL of 1:1 mixture ofdioxane-H₂O is added KOH (4.72 g, 84.2 mmol). The mixture is stirred atroom temperature overnight. The solution is extracted with Et₂O (100 mL)and the aqueous layer is then acidified with HCl to a pH of less than 2followed by extraction with EtOAc (80 mL×3). The EtOAc layers arecombined, washed with brine, and dried with Na₂SO₄. After removal ofsolvent, 3-[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-propionic acid isobtained. It was used without further purification; ¹H NMR (DMSO-d₆) δ2.47 (t, 2H, J=7.2 Hz), 3.39 (q, 2H, J=6.0 Hz), 6.90 (s, 1H), 8.17 (t,1H, J=4.8 Hz); m/z [M⁺+1] 340.9.

A mixture of P₂O₅ (100 mg) in PPA (2 g) is stirred and heated at 120° C.for 1 hour.

After cooling to 100° C.,3-[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-propionic acid (100 mg) isadded. The mixture is stirred vigorously for 2.5 hours and then cooledto room temperature. Ice-water is added and the solution is neutralizedto pH4 by adding NaOH.2,3-Dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione iscollected, as precipitate, by filtration; ¹H NMR (DMSO-d₆) δ 2.71-2.78(m, 2H), 3.32-3.40 (m, 2H), 8.50 (s, 1H); m/z [M⁺+1] 322.9.

To a solution of2,3-dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione (2.5 g,7.74 mmol) in a mixture of DMF-MeOH (6 mL) is added NaBH₄ (1.47g, 38.7mmol). The mixture is stirred at room temperature overnight. It isconcentrated and water is added. The mixture is extracted with EtOAc,washed with brine and dried. After the solvent is removed, the residueis subjected to silica gel column chromatography and eluted withCH₂Cl₂—MeOH to give2,3-dibromo-4-hydroxy-4.5,6.7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;¹H NMR (DMSO-d₆) δ 1.74-1.84 (m, 1H), 2.01-2.10 (m, 1H), 3.00-3.10 (m,1H), 3.42-3.50 (m, 1H), 4.63-4.68 (m, 1H), 5.06 (d, 1H, J=6.4 Hz), 7.92(d, 1H, J=4.4 Hz); m/z [M⁺+1] 324.9.

The following reference compounds are synthesized by a similar procedureas outlined in reference 1 using appropriate starting materials:

Reference 22,3-Dichloro-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one

3-[(4,5-Dichloro-1H-pyrrole-2-carbonyl)-amino]-propionic acid; ¹H NMR(DMSO-d₆) δ 2.50 (t, 2H, J=6.8 Hz), 3.43 (q, 2H, J=6.8 Hz), 6.90 (s,1H), 8.23 (t, 1H, J=4.4 Hz), 12.20 (bs, 1H), 12.72 (s, 1H); m/z [M⁺+1]250.9.

2,3-Dichloro-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione: ¹H NMR(DMSO-d₆) δ 2.72-2.78 (m, 2H), 3.38-3.42 (m, 2H), 8.54 (t, 1H, J=4.8Hz), 13.52 (bs, 1H); m/z [M⁺+1] 232.9.

2,3-Dichloro-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one:¹H NMR (DMSO-d₆) δ 1.75-1.84 (m, 1H), 2.00-2.10 (m, 1H), 3.00-3.08 (m,1H), 3.42-3.50 (m, 1H), 4.68-4.72 (m, 1H), 5.13 (d, 1H, J=5.6 Hz), 7.93(t, 1H, J=4.4 Hz), 12.43 (bs, 1H); m/z [M⁺+1] 235.0.

Reference 34-Hydroxy-6-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one

6-Methyl-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione: ¹H NMR(DMSO-d₆) δ 1.21 (d, 3H, J=6.8 Hz), 2.62 (d, 1H, J=16.8 Hz), 2.78 (dd,1H, J₁=6.0 Hz, J₂=16.8 Hz), 3.76-3.84 (m, 1H), 6.54 (d, 1H, J=2.4 Hz),6.97 (d, 1H, J=5.6 Hz), 8.13 (d, 1H, J=2.4 Hz), 12.12 (s, 1H); m/z[M⁺+1] 179.0.

4-Hydroxy-6-methyl-4,5 6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one: ¹HNMR (DMSO-d₆) δ 1.19 (d, 3H, J=6.8 Hz), 1.68-1.78 (m, 1H), 1.96-2.08 (m,1H), 3.44-3.56 (m, 1H), 4.66-4.72 (m, 1H), 5.02 (d, 1H, J=6.8 Hz), 6.19(t, 1H, J=3.2 Hz), 6.81 (d, 1H, J=3.2 Hz), 7.18 (s, 1H), 11.06 (s, 1H);m/z [M⁺+1] 181.1.

Reference 42,3-Dibromo-4-hydroxy-6-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one

To a solution of4-hydroxy-6-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one(18mg, 0.1 mmol) in THF (5mL) is added NBS (35.6g, 0.2 mmol) at roomtemperature. It is stirred for 1 hour and concentrated. Sodiumthiosulfate aqueous solution is added to the residue. The mixture isextracted with EtOAc twice. The organic layers are combined and dried togive2,3-dibromo-4-hydroxy-6-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;¹H NMR (DMSO-d₆) δ 1.16 (d, 3H, J=7.2 Hz), 1.79-1.85 (m, 1H), 2.12-2.19(m, 1H), 3.39-3.43 (m, 1H), 4.65-4.72 (m, 1H), 4.91 (d, 1H, J=6.8 Hz),7.67 (s, 1H), 11.04 (s, 1H); m/z [M⁺+1] 338.9.

Reference 67-Bromo-5-hydroxy-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one

7-Bromo-3,4-dihydro-2H,10H-azepino[3,4-b]indole-1,5-dione: ¹H NMR(DMSO-d₆) δ 2.82-2.88 (m, 2H), 3.43-3.51 (m, 2H), 7.45-7.51 (m, 2H),8.44 (s, 1H), 8.81 (s, 1H), 12.66 (s, 1H); m/z [M⁺+1] 293.0.

7-Bromo-5-hydroxy-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one: ¹HNMR (DMSO-d₆) δ 1.97-2.06 (m, 1H), 2.08-2.16 (m, 1H), 3.10-3.21 (m, 1H),3.43-3.52 (m, 1H), 5.09-5.13 (m, 1H), 5.32 (d, 1H, J=6.4 Hz), 7.31 (d,1H, J=8.0 Hz), 7.37 (d, 1H, J=8.0 Hz), 7.94 (s, 1H), 8.20 (s, 1H), 11.48(s, 1H); m/z [M₊+1] 295.0.

Reference 7 5-Hydroxy-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one

3,4-Dihydro-2H,10H-azepino[3,4-b]indole-1,5-dione: ¹H NMR (DMSO-d₆) δ2.82-2.86 (m, 2H), 3.44-3.50 (m, 2H), 7.25 (t, 1H, J=7.2 Hz), 7.32 (d,1H, J=7.2 Hz), 7.53 (d, 1H, J=8.0 Hz), 8.30 (d, 1H, J=8.0 Hz), 8.74 (t,1H, J=5.2 Hz), 12.46 (s, 1H); m/z [M⁺+1] 215.0.

5-Hydroxy-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one: ¹H NMR(DMSO-d₆) δ 1.96-2.06 (m, 1H), 2.10-2.20 (m, 1H), 3.10-3.20 (m, 1H),3.46-3.56 (m, 1H), 5.10-5.17 (m, 1H), 5.20 (d, 1H, J=6.8 Hz), 7.04 (t,1H, J=7.2 Hz), 7.19 (t, 1H, J=6.8 Hz), 7.41 (d, 1H, J=7.2 Hz), 7.78 (d,1H, J=6.8 Hz), 8.13 (s, 1H), 11.25 (s, 1H); m/z [M⁺+1] 217.1.

Reference 87-Bromo-3-methyl-3,4-dihydro-2H,10H-azepino[3.4-b]indole-1,5-dione

¹H NMR (DMSO-d₆) δ 1.24 (d, 3H, J=6.8 Hz), 2.73 (d, 1H, J=16.4 Hz), 2.92(dd, 1H, J₁=10.4 Hz, J₂=16.4 Hz), 3.90-4.00 (m, 1H), 7.43-7.50 (m, 2H),8.41 (d, 1H, J=1.0 Hz), 8.66 (d, 1H, J=3.6 Hz); m/z [M⁺+1] 309.0.

Reference 97-Chloro-5-hydroxy-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one

¹H NMR (DMSO-d₆) δ 1.96-2.04 (m, 1H), 2.08-2.16 (m, 1H), 3.10-3.18 (m,1H), 3.42-3.50 (m, 1H), 5.09 (q, 1H, J=5.2 Hz), 5.28 (d, 1H, J=7.2 Hz),7.18 (dd, 1H, J₁=1.6 Hz, J₂=8.8 Hz), 7.39 (d, 1H, J=8.8 Hz), 7.77 (d,1H, J=1.6 Hz), 8.18 (t, 1H, J=4.8 Hz), 11.45 (s, 1H); m/z [M⁺+1] 251.0.

Reference 10 (1-Oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-aceticacid

A solution of5-ethoxycarbonylmethylene-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylicacid di-tert-butyl ester, (0.496 g, 1.02 mmol) and LiOH (0.246 g, 10.2mmol) in MeOH—H₂O (1:1 mixture, 50 mL) is stirred at room temperaturefor 2 days before it is concentrated. Water is added to the residue andit is acidified with NaHSO₄ (2M). The solid that is precipitated iscollected by vacuum filtration and dried to yield(1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid; ¹H NMR(DMSO-d₆) δ 2.50 (t, 2H, J=5.6 Hz), 2.82 (s, 1H), 5.00 (t, 1H, J=6.4Hz), 6.18 (t, 1H, J=7.2 Hz), 6.34 (t, 1H, J=7.2 Hz), 6.56 (d, 1H, J=8.8Hz), 6.90 (d, 1H, J=8.8 Hz), 7.21 (t, 1H, J=4.4 Hz), 10.98 (s, 1H); m/z[M⁺+1] 257.0.

Reference 11 5-Fluoro-1H-indole-2-carboxylic acid(3-hydroxy-propyl)-amide

To a solution of 5-fluoro-1H-indole-2-carboxylic acid (2.27 g, 12.7mmol) in CH₂Cl₂ (100 mL) is added DMAP (4.64 g, 38 mmol), EDCI (3.64 g,19 mmol), 3-amino-propan-1-ol (1.90 g, 25 mmol). The mixture is stirredat room temperature for 24 hours. After the solvent is removed undervacuum, 5% HCl (100 mL) is added to the mixture. It is extracted withEtOAc (100 mL×3). The combined organic layers are washed with saturatedaqueous NaHCO₃ (100 mL), brine (100 mL) and dried with Na₂SO₄. Solventis removed to give 5-fluoro-1H-indole-2-carboxylic acid(3-hydroxy-propyl)-amide; ¹H NMR (DMSO-d₆) δ 1.69 (quint, 2H, J=6.4 Hz),3.34 (q, 2H, J=6.0 Hz), 3.48 (t, 2H, J=6.4 Hz), 4.48 (bs, 1H), 6.99-7.10(m, 2H), 7.36-7.44 (m, 2H), 8.47 (t, 1H, J=5.6 Hz), 11.63 (s, 1H); m/z[M⁺+1] 237.1.

Reference 12 5-Fluoro-3-iodo-1H-indole-2-carboxylic acid(3-hydroxy-propyl)-amide

To a solution of 5-fluoro-1H-indole-2-carboxylic acid(3-hydroxy-propyl)-amide, prepared as in reference 11, (4.89 g, 20.7mmol) in DMF (100 mL) is added KOH (3.48 g, 62 mmol) and 12 (5.78 g,22.8 mmol). It is stirred at room temperature for 1 hour andconcentrated. Water is added to the residue and the mixture is acidifiedwith HCl. The mixture is extracted with EtOAc (100 mL×2). The combinedorganic layers are washed with Na₂S₂O₃ (1M, 50 mL), brine (100 mL), anddried with Na₂SO₄. Solvent is removed to give5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide; ¹HNMR (DMSO-d₆) δ 1.73 (quint, 2H, J=6.0 Hz), 3.39 (q, 2H, J=6.0 Hz), 3.54(t, 2H, J=6.0 Hz), 4.54 (bs, 1H), 7.06-7.16 (m, 2H), 7.46 (dd, 1H,J₁=4.4 Hz, J₂=8.8 Hz), 8.00 (t, 1H, J=6.0 Hz), 12.10 (s, 1H); m/z [M⁺+1]363.0.

Reference 13 5-Fluoro-3-iodo-1H-indole-2-carboxylic acid(3-oxo-propyl)-amide

To a solution of oxalyl chloride (3.68 g, 30 mmol) in anhydrous CH₂Cl₂(50 mL) at −40° C. is added DMSO (4.52 g, 57.9 mmol) drop-wise. Themixture is stirred at this temperature for 5 minutes.5-Fluoro-3-iodo-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide,prepared as in reference 12, (6.99 g, 19.3 mmol) is dissolved in CH₂Cl₂(800 mL) with small amount of DMSO (10 mL) and added to theabove-mentioned solution at −40° C. The reaction is stirred foradditional 30 minutes before adding Et₃N (11.7 g, 0.116 mol). Themixture is allowed to warm to room temperature and quenched with H₂O (1L). The organic layer is separated and washed with citric acid (10%, 500mL), saturated NaHCO₃ (500 mL) and brine (500 mL). It is dried withNa₂SO₄ to give 5-fluoro-3-iodo-1H-indole-2-carboxylic acid(3-oxo-propyl)-amide; ¹H NMR (DMSO-d₆) δ 2.75 (dt, 2H, J₁=1.2 Hz, J₂=6.0Hz), 3.61 (q, 2H, J=5.2 Hz), 7.06-7.17 (m, 2H), 7.45 (dd, 1H, J₁=4.8 Hz,J₂=8.8 Hz), 8.11 (t, 1H, J=5.6 Hz), 9.74 (t, 1H, 1.2 Hz), 12.10 (s, 1H);m/z [M⁺+1] 361.0.

Reference 145-[(5-Fluoro-3-iodo-1H-indole-2-carbonyl)-amino]-pent-2-enoic acid ethylester

To a solution of 5-fluoro-3-iodo-1H-indole-2-carboxylic acid(3-oxo-propyl)-amide, prepared as in reference 13, (5.86 g, 16.3 mmol)in THF (200 mL) is added (carbethoxymethylene) triphenylphosphorane (18g, 51.7 mmol) at 0° C. The reaction is stirred at room temperatureovernight. It is washed with saturated NH₄Cl (200 mL) and extracted withEt₂O (200 mL×2). The combined organic layers are washed with brine anddried. It is concentrated and purified by silica gel columnchromatography and eluted with EtOAc-Hexanes to give5-[(5-fluoro-3-iodo-1H-indole-2-carbonyl)-amino]-pent-2-enoic acid ethylester as the trans isomer; ¹H NMR (DMSO-d₆) δ 1.25 (t, 3H, J=6.8 Hz),2.52 (t, 2H, J=6.8 Hz), 3.48 (q, 2H, J=5.6 Hz), 4.10 (q, 2H, 6.8 Hz),5.96 (d, 1H, J=15.6 Hz), 6.96 (dt, 1H, J₁=5.8 Hz, J₂=15.6 Hz), 7.06-7.18(m, 2H), 7.46 (dd, 1H, J₁=4.0 Hz, J₂=8.8 Hz), 8.11 (t, 1H, J=6.4 Hz),12.10 (s, 1H); m/z [M⁺+1] 431.0.

Reference 152-[tert-Butoxycarbonyl-(4-ethoxycarbonyl-but-3-enyl)-aminocarbonyl]-5-fluoro-3-iodo-indole-1-carboxylicacid tert-butyl ester

To a solution of5-[(5-fluoro-3-iodo-1H-indole-2-carbonyl)-amino]-pent-2-enoic acid ethylester, prepared as in reference 14, (4.15 g, 9.65 mmol) in MeCN (100 mL)is added DMAP (2.59 g, 21.2 mmol) and di-tert-butyl dicarbonate (6.33 g,28.9 mmol). The reaction is stirred at room temperature overnight. It isconcentrated and EtOAc (100 mL) is added. It is washed with NaHSO₄ (2M,100 mL) and brine (100 mL). The organic layer is dried, concentrated andpurified by silica gel column chromatography and eluted withEtOAc-Hexanes to give2-[tert-butoxycarbonyl-(4-ethoxycarbonyl-but-3-enyl)-aminocarbonyl]-5-fluoro-3-iodo-indole-1-carboxylicacid tert-butyl ester; ¹H NMR (CDCl₃) δ 1.29 (t, 3H, J=7.2 Hz), 1.54 (s,9H), 1.60 (s, 9H), 2.71 (q, 2H, J=7.2 Hz), 3.86-3.94 (m, 1H), 4.16-4.21(m, 1H), 4.19 (q, 2H, J=7.2 Hz), 5.99 (d, 1H, J=15.6 Hz), 6.98-7.14 (m,3H), 8.06 (dd, 1H, J₁=4.4 Hz, J₂=8.8 Hz); m/z [M⁺+Na] 653.1.

Reference 16(7-Fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-aceticacid

A suspension of triphenylphosphine (3.36 g, 12.8 mmol), Pd(OAc)₂ (1.44g, 6.40 mmol) and Ag₂CO₃ (3.53 g, 12.8 mmol) in anhydrous THF (100 mL)is stirred at room temperature for 15 minutes. A solution of2-[tert-butoxycarbonyl-(4-ethoxycarbonyl-but-3-enyl)-aminocarbonyl]-5-fluoro-3-iodo-indole-1-carboxylicacid tert-butyl ester (4.03 g, 6.40 mmol), prepared as in reference 15,in THF (10 mL) is added to the above prepared suspension. The mixture isheated at 60° C. for 16 hours. The inorganic precipitate is removed andthe organic layer is concentrated. The residue is purified by silica gelcolumn chromatography and eluted with EtOAc-Hexanes to give the5-ethoxycarbonylmethylene-7-fluoro-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylicacid di-tert-butyl ester; ¹H NMR (CDCl₃) δ 1.34 (t, 3H, J=7.6 Hz), 1.57(s, 9H), 1.60 (s, 9H), 3.46-3.52 (m, 2H), 4.13 (t, 2H, J=4.8 Hz), 4.24(q, 2H, J=7.6 Hz), 6.30 (t, 1H, J=2.8 Hz), 7.21 (td, 1H, J₁=2.8 Hz,J₂=9.2 Hz), 7.42 (dd, 1H, J₁=2.8 Hz, J₂=8.8 Hz), 8.10 (dd, 1H, J₁=4.0Hz, J₂=9.2 Hz); m/z [M⁺+Na] 525.0.

To a solution of5-ethoxycarbonylmethylene-7-fluoro-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylicacid di-tert-butyl ester, (1.31g, 2.6mmol) in MeOH—H₂O (3:1 mixture, 150mL) is added LiOH (0.312 g, 13 mmol). The mixture is stirred at roomtemperature for 2 days and concentrated. Water (100 mL) is added to theresidue and it is acidified with 2M NaHSO₄. The precipitate is collectedby filtration and dried to give(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-aceticacid; ¹H NMR (DMSO-d₆) δ 2.26 (d, 2H, J=5.2 Hz), 2.79 (s, 2H), 5.00 (t,1H, 6.4 Hz), 6.22 (dt, 1H, J₁=2.4 Hz, J₂=10.8 Hz), 6.56 (dd, 1H, J₁=4.0Hz, J₂=8.8 Hz), 6.66 (dd, 1H, J₁=2.4 Hz, J₂=10.8 Hz), 7.26 (t, 1H, J=5.6Hz), 11.10 (s, 1H); m/z [M⁺+1] 275.0.

Reference 17(7-Fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetylazide

To an ice-cold solution of(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-aceticacid (0.99 g, 3.6 mmol) and triethylamine (0.36 g, 3.6 mmol) in dry DMF(10 mL) was added in dropwise a solution of diphenylphosphoryl azide(0.99 g, 3.6 mmol), in DMF (5 mL) over a period of 2 h. After removal ofthe cooling bath, the mixture was stirred at room temperature for 12 h.It was poured into ice and the precipitate therefore formed wascollected by vacuum filtration, which appeared to be the title compound(0.10 g). Extract the rest part of the mixture with ethyl acetate (20mL×2). The organic layers were combined, washed with saturated aqueousNaHCO₃, brine, and dried over anhydrous Na₂SO₄. It was concentrated andthe oil obtained was treated with diethyl ether to give additional titlecompound as a solid precipitate (0.23 g).

Example 14-(2-Amino-3H-imidazol-4-yl)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one

To a solution of2,3-dichloro-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one(60 mg, 0.256 mmol), prepared as in reference 2, in methanesulfonic acid(0.5 mL) is added 2-aminoimidazole sulfate (40.5 mg, 0.153 mmol). Themixture is stirred at 45° C. overnight, cooled to room temperature andEt₂O (5 mL) is added resulting in brown oil. After discarding thesupernatant, the oil is purified by silica gel column chromatography andeluted with MeOH—CH₂Cl₂ to give4-(2-amino-3H-imidazol-4-yl)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;¹H NMR (Methanol-d₄) δ 2.09-2.17 (m, 1H), 2.23-2.31 (m, 1H), 3.20-3.29(m, 2H), 4.23 (t, 1H, J=3.6 Hz), 6.18 (s, 1H); m/z [M⁺+1] 300.0.

Example 24-(2-Amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one

To a solution of4-(2-amino-3H-imidazol-4-yl)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one,prepared as in reference 2, (38 mg, 0.13 mmol) in AcOH (3 mL) is addedNaOAc trihydrate (86 mg, 0.63 mmol). A solution of Br₂ (40 mg, 0.25mmol) in AcOH (1 mL) is added drop-wise, the mixture is stirred for anadditional 30 minutes and concentrated. The residue is purified by HPLC(C₁₈ column, eluted with CH₃CN—H₂O containing 0.05% TFA) to give4-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;¹H NMR (DMSO-d₆) δ 3.18-3.26 (m, 2H), 3.26-3.32 (m, 2H), 8.09 (t, 1H,J=4.8 Hz), 8.68 (s, 1H), 9.37 (s, 2H), 11.11 (s, 1H), 13.46 (s, 1H); m/z[M⁺+1] 314.0.

Example 32-[N′-(2,3-Dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoicacid

To a solution of2,3-dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione (32.2 mg,0.10 mmol) in EtOH (5 mL) is added 2-hydrazinobenzoic acid (22.6 mg,0.12 mmol) and HCl in i-PrOH (6N, 0.3 mL). The mixture is refluxed for 2hours and then concentrated under reduced pressure. The residue ispurified by HPLC (C₁₈ column, eluted with CH₃CN/H₂O with 0.05% TFA) togive2-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoicacid; ¹H NMR (DMSO-d₆) δ 2.80-2.86 (m, 2H), 3.30-3.34 (m, 2H), 6.82 (t,1H, J=8.0 Hz), 7.51 (d, 1H, J=7.2 Hz), 7.83-7.88 (m, 2H), 8.13 (t, 1H,J=6.0 Hz), 11.03 (s, 1H), 12.95 (s, 1H), 13.13 (s, 1H); m/z [M⁺+1]456.9.

Example 45-(2-Amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one

To a solution of5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-bromo-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-oneTFA salt (13 mg, 0.027 mmol), in MeOH (5 mL) is added sodium acetatetrihydrate (24 mg, 0.18 mmol) and 10% Pd/C (4.5 mg). It is stirred atroom temperature under a hydrogen atmosphere overnight and then thecatalyst is removed by filtration. The solution is concentrated and theresidue is purified by HPLC (C₁₈ column, eluted with CH₃CN/H₂O with0.05% TFA) to give5-(2-amino-5-oxo-3.5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;¹H NMR (DMSO-d₆) δ 3.30-3.36 (m, 4H), 7.20 (t, 1H, J=7.6 Hz), 7.33 (t,1H, J=7.2 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.58 (d, 1H, J=7.2 Hz), 8.36 (t,1H, J=2.4 Hz), 9.20 (bs, 1H), 10.37 (bs, 1H), 12.45 (s, 1H); m/z [M⁺+1]296.1.

Example 59-Amino-5-(2-amino-5-oxo-3.5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one

To a solution of5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-9-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-oneTFA salt (4 mg, 8.8 μmol) in MeOH (3 mL) is added 10% Pd/C (10 mg). Themixture is stirred at room temperature under hydrogen atmosphereovernight and then the catalyst is removed by filtration. The solutionis concentrated and the residue purified by HPLC (C₁₈ column, elutedwith CH₃CN/H₂O with 0.05% TFA) to give9-amino-5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;¹H NMR (MeOD-d₄) δ 3.48-3.53 (m, 4H), 7.358 (d, 1H, J=6.0 Hz), 7.362 (d,1H, J=3.2 Hz), 7.63 (dd, 1H, J₁=3.2 Hz, J₂=6.0 Hz); m/z [M⁺+1] 311.1.

Example 6 (1-Oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-aceticacid

To a solution of(1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid,prepared as in reference 10, (15 mg, 0.062 mmol) in DMF (1 mL) is addedDIEA (24 mg, 0.186 mmol), HATU (26 mg, 0.068 mmol) and 2-aminopyridine(17 mg, 0.186 mmol). The mixture is stirred at room temperature for 2hours and concentrated. The residue is purified by HPLC (C₁₈ column,eluted with CH₃CN/H₂O with 0.05% TFA) to give(1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid; ¹H NMR(DMSO-d₆) δ 3.40 (t, 2H, J=5.6 Hz), 3.94 (s, 2H), 5.94 (t, 1H, J=7.2Hz), 7.06 (t, 2H, J=6.8 Hz), 7.23(dd, 1H, J₁=6.8 Hz, J₂=14 Hz), 7.46 (d,1H, J=8.0 Hz), 7.71 (t, 1H, J=8.0 Hz), 7.95 (d, 2H, J=8.0 Hz), 8.13 (t,1H, J=5.2 Hz), 8.28 (d, 1H, J=3.6 Hz), 10.59 (s, 1H), 11.89 (s, 1H); m/z[M⁺+1] 333.1.

Example 7N-(6-Chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide

To a solution of(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-aceticacid, prepared as in reference 16, (25 mg, 0.091 mmol) in DMF (1 mL) isadded DIEA (35.4 mg, 0.274 mmol), HATU (38.2 mg, 0.100 mmol) and6-chloro-pyridin-3-ylamine (35.2 mg, 0.274 mmol). The mixture is stirredat room temperature for 2 hours and concentrated. The residue ispurified by HPLC (C₁₈ column, eluted with CH₃CN/H₂O with 0.05% TFA) togiveN-(6-Chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J=5.6 Hz), 3.84 (s, 2H), 5.96 (t, 1H,J=7.2 Hz), 7.12 (dt, 1H, J₁=2.4 Hz, J₂=8.8 Hz), 7.43 (d, 1H, J=8.8 Hz),7.46 (dd, 1H, J₁=4.4 Hz, J₂=8.8 Hz), 7.67 (dd, 1H, J₁=2.4 Hz, J₂=10.8Hz), 8.01 (dd, 1H, J₁=2.8 Hz, J₂=8.0 Hz), 8.19 (t, 1H, J=5.2 Hz), 8.54(d, 1H, J=3.2 Hz), 10.48 (s, 1H), 12.04 (s, 1H); m/z [M⁺+1] 385.0.

Example 81-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-3-yl-urea

A suspension of(7-Fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetylazide, prepared as in reference 17, (10 mg, 0.33 mmol) in dry toluene (1mL) is heated at 110° C. for 15 minutes. To this mixture is addedpyridin-3-ylamine (16 mg, 0.17 mmol) and it is heated at the sametemperature for 1 hour. Toluene is removed in vacuum and the residue ispurified by HPLC (C₁₈ column, eluted with CH₃CN/H₂O with 0.5% TFA) toafford1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-3-yl-urea;¹H NMR (DMSO-d₆) δ 2.73-2.78 (m, 2H), 3.33-3.37 (m, 2H), 7.10-7.18 (m,2H), 7.43-7.48 (m, 2H), 8.69 (d, 1H, J=10.8 Hz), 8.87 (s, 1H), 9.46 (s,1H), 10.66 (s, 1H); m/z [M⁺+1] 366.1.

Example 9N-(2-Dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide

A suspension of(7-Fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetylazide, prepared as in reference 17, (10 mg, 0.33 mmol) andN,N-dimethylethylene-diamine (15 mg, 0.17 mmol) in dry toluene (1 mL) isheated at 110° C. for 1 hour. Toluene is removed in vacuum and theresidue is purified by HPLC (C₁₈ column, eluted with CH₃CN/H₂O with 0.5%TFA) to affordN-(2-dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;¹H NMR (DMSO-d₆) δ 2.85 (s, 6H), 3.19-3.22 (m, 2H), 3.25-3.30 (m, 2H),3.44-3.48 (m, 2H), 3.49 (q, 2H, J=6.8 Hz), 6.34 (s, 1H), 7.18 (dt, 1H,J₁=2.8 Hz, J₂=8.8 Hz), 7.50 (dd, 1H, J₁=4.4 Hz, J₂=8.8 Hz), 7.74 (dd,1H, J₁=2.8 Hz, J₂=10.4 Hz), 8.39-8.44 (m, 2H), 9.36 (bs, 1H), 12.12 (s,1H); m/z [M⁺+1] 345.1.

The following examples of Table 1 are synthesized by similar procedures,as outlined in the above examples, using appropriate starting materials:TABLE 1 Compound Structure Physical Data 3

¹H NMR (Methanol-d₄) δ 1.28 (t, 3H, J = 7.2 Hz), 2.12-2.22 (m, 1H),2.28-2.36 (m, 1H), 3.26-3.34 (m, 4H), 4.24 (t, 1H, J = 4.4 Hz), 6.20 (s,1H); m/z [M⁺ + 1] 417.9. 4

¹H NMR (DMSO-d⁶) δ 2.08 (s, 3H), 3.22-3.30(m, 4H), 7.99 (t, 1H,J = 4.4Hz), 13.15 (s, 1H); m/z [M⁺ + 1] 445.9. 5

¹H NMR (DMSO-d₆) δ 1.15 (t, 3H, J = 7.2 Hz), 3.20-3.40 (m, 4H), 3.71 (q,2H, J = 7.2 Hz), 8.09 (t, 1H, J = 2.4 Hz), 13.44 (s, 1H); m/z [M⁺ + 1]431.9. 6

¹H NMR (DMSO-d₆) δ 1.21 (d, 3H, J = 6.8 Hz), 2.90-3.00 (m, 1H),3.64-3.72 (m, 2H), 7.91 (t, 1H, J = 4.4 Hz), 8.62 (bs, 1H), 9.40 (bs,1H), 11.01 (bs, 1H), 13.37 (s, 1H); m/z [M⁺ + 1] 417.9. 7

¹H NMR (MeOD-d₄) δ 2.23-2.28 (m, 2H), 3.23-3.24 (m, 2H), 4.55 (t, 1H, J= 5.2 Hz), 6.12 (s, 1H), 7.27 (dd, 1H, J₁ = 1.4 Hz, J₂ =8.8 Hz), 7.35(d, 1H, J = 8.8 Hz), 7.46 (d, 1H, J = 1.4 Hz); m/z [M⁺ + 1] 360.0. 8

¹H NMR (MeOD-d₄) δ 2.27-2.33 (m, 2H), 3.32-3.37 (m, 2H), 4.59 (t, 1H, J= 4.8 Hz), 6.20 (s, 1H), 7.14 (d, 1H, J = 8.8 Hz), 7.30 (s, 1H), 7.41(d, 1H, J = 8.8 Hz); m/z [M⁺ + 1]316.1. 9

¹H NMR (MeOD-d₄) δ 2.37-2.43 (m, 2H), 3.44 (q, 2H, J=5.4 Hz), 4.77 (t,1H, J = 5.4 Hz), 6.30 (s, 1H), 7.24 (t, 1H, J = 8.0 Hz), 7.89 (d, 1H, J= 8.0 Hz), 8.25 (d, 1H, J = 8.0 Hz); m/z [M⁺ + 1] 327.1. 10

¹H NMR (MeOD-d₄) δ 3.45-3.50 (m, 4H), 7.46-7.54 (m, 2H), 7.78 (d, 1H, J= 1.2 Hz); m/z [M⁺ + 1] 374.0. 11

¹H NMR (MeOD-d₄) δ 3.44-3.52(m, 4H), 7.36 (dd, 1H, J₁ = 2.8 Hz, J₂ = 8.8Hz), 7.57 (d, 1H, J = 8.8 Hz), 7.63 (d, 1H, J = 1.2 Hz); m/z [M⁺ + 1]330.0. 12

¹H NMR (DMSO-d₆) δ 3.20-3.50 (m, 4H), 7.17 (dt, 1H, J₁ = 2.0 Hz, J₂ =9.6 Hz), 7.41 (dd, 1H, J₁ = 2.4 Hz, J₂ = 9.6 Hz), 7.52 (dd, 1H, J₁ = 2.8Hz, J₂ = 8.8 Hz), 8.37 (bs, 2H), 9.18 (bs, 1H), 10.49 (bs, 1H), 12.51(bs, 1H); m/z [M⁺ + 1] 314.1. 13

¹H NMR (MeOD-d₄) δ 3.49-3.54 (m, 4H), 7.48 (t, 1H, J = 8.0 Hz), 8.10 (d,1H, J = 8.0 Hz), 8.38 (d, 1H, J = 8.0 Hz); m/z [M⁺ + 1]341.1. 14

¹H NMR (MeOD-d₄) δ 2.17 (s, 3H), 3.46-3.51 (m, 2H), 3.52-3.58 (m, 2H),7.40-7.50 (m, 2H), 7.78 (s, 1H); m/z [M⁺ + 1] 416.0. 15

¹H NMR (DMSO-d₆) δ 1.25 (d, 3H, J = 6.8 Hz), 3.00-3.20 (m, 1H),3.30-3.55 (m, 2H), 7.38-7.50 (m, 2H), 7.83 (s, 1H), 8.26 (d, 1H, J = 2.8Hz), 8.47 (s, 2H), 9.30 (s, 1H), 10.57 (s, 1H), 12.56 (s, 1H); m/z [M⁺ +1] 388.0. 16

¹H NMR (DMSO-d₆) δ 3.33-3.40 (m, 4H), 7.67 (d, 1H, J = 8.8 Hz), 8.17(dd, 1H, J₁ =2.4 Hz, J₂ = 8.8 Hz), 8.52 (t, 1H, J = 5.2 Hz), 8.50-8.54(bs, 1H), 8.60 (d, 1H, J = 2.4 Hz), 9.18 (bs, 1H), 10.80 (bs, 1H), 13.04(bs, 1H); m/z [M⁺ + 1] 341.0. 17

¹H NMR (DMSO-d₆) δ 3.30-3.36 (m, 4H), 7.26 (d, 1H, J = 8.0 Hz), 7.44 (s,1H), 7.56 (d, 1H, J = 8.0 Hz), 8.42 (t, 1H, J = 5.2 Hz), 8.80 (bs, 1H),10.60(bs, 2H), 12.59 (bs, 1H); m/z [M⁺ + 1] 311.1. 18

¹H NMR (DMSO-d₆) δ 3.20 (s, 2H), 3.34-3.40 (m, 4H), 7.70 (d, 1H, J = 8.8Hz), 7.81 (dd, 1H, J₁ = 2.4 Hz, J₂ = 8.8 Hz), 8.19(d, 1H, J = 2.4 Hz),8.40 (bs, 1H), 8.48 (t, 1H, J = 5.2 Hz), 9.10 (bs, 1H), 10.70 (bs, 1H),12.88 (bs, 1H); m/z [M⁺ + 1] 374.1. 19

¹H NMR (DMSO-d₆) δ 2.80-2.86 (m, 2H), 3.30-3.34 (m, 2H), 7.33 (d, 2H, J= 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz), 8.10 (t, 1H, J = 5.2 Hz), 9.57 (s,1H), 12.28 (bs, 1H), 12.89 (s, 1H); m/z [M⁺ + 1] 456.9. 20

¹H NMR (DMSO-d₆) δ 2.92-2.96 (m, 2H), 3.40-3.28 (m, 2H), 7.03 (t, 1H, J= 6.8 Hz), 7.50 (d, 1H, J = 8.7 Hz), 8.00 (t, 1H, J = 8.0 Hz), 8.15, (d,1H, J = 5.2 Hz), 8.20 (t, 1H, J =5.4 Hz), 10.91 (bs, 1H), 13.14 (s, 1H);m/z [M⁺ + 1] 413.9. 21

¹H NMR (DMSO-d₆) δ 2.84-2.90 (m, 2H), 3.31-3.36 (m, 2H), 7.42 (d, 2H, J= 8.8 Hz), 8.10-8.18 (m, 3H), 10.07 (s, 1H), 12.98 (s, 1H); m/z [M⁺ + 1]457.9. 22

¹H NMR (DMSO-d₆) δ 2.80-2.86 (m, 2H), 3.30-3.36 (m, 2H), 7.04 (bs, 2H),7.37 (d, 2H, J = 8.8 Hz), 7.65 (d, 2H, J = 8.8 Hz), 8.10 (t, 1H, J = 5.6Hz), 9.57 (s, 1H), 12.90 (s, 1H); m/z [M⁺ + 1] 491.9. 23

¹H NMR (DMSO-d₆) δ 3.06-3.12 (m, 2H), 3.40-3.46 (m, 2H), 7.02 (t, 1H, J= 6.0 Hz), 7.21 (t, 1H, J = 7.2 Hz), 7.31 (t, 1H, J = 7.2 Hz), 7.43 (d,1H, J = 8.8 Hz), 7.49 (d, 1H, J =8.0 Hz), 8.02 (t, 1H, J = 7.2 Hz), 8.12(d, 1H, J = 5.6 Hz), 8.35 (d, 1H, J = 8.0 Hz), 8.46 (t, 1H, J = 4.8 Hz),10.92 (bs, 1H), 12.07 (s, 1H); m/z [M⁺ + 1] 306.1. 24

¹H NMR (DMSO-d₆) δ 3.06-3.11 (m, 2H), 3.40-3.46 (m, 2H), 7.03 (t, 1H, J= 6.4 Hz), 7.33 (dd, 1H, J₁ = 6.1 Hz, J₂ = 8.8 Hz), 7.38 (d, 1H, J = 8.8Hz), 7.50 (d, 1H, J = 8.8 Hz), 8.02 (t, 1H, J = 7.6 Hz), 8.13 (d, 1H, J= 5.2 Hz), 8.33 (d, 1H, J = 1.6 Hz), 8.54 (t, 1H, J =5.2 Hz), 10.99 (bs,1H), 12.27 (s, 1H); m/z [M⁺ + 1] 340.0. 25

¹H NMR (DMSO-d₆) δ 3.04-3.10 (m, 2H), 3.40-3.46 (m, 2H), 7.01 (t, 1H, J= 6.4 Hz), 7.37 (d, 1H, J = 8.8 Hz), 7.45 (s, 2H), 7.99 (t, 1H, J = 7.6Hz), 8.14 (d, 1H, J = 5.2 Hz), 8.50 (s, 1H), 8.53 (t, 1H, J = 5.2 Hz),10.84 (bs, 1H), 12.26 (s, 1H); m/z [M⁺ + 1] 384.0. 26

¹H NMR (DMSO-d₆) δ 3.04-3.10 (m, 2H), 3.39-3.44 (m, 2H), 6.53 (d, 1H, J= 7.5 Hz), 6.93-7.01 (m, 2H), 7.41 (d, 1H, J = 8.4 Hz), 7.64 (d, 1H, J =8.0 Hz), 7.98 (t, 1H, J = 8.0 Hz), 8.12 (d, 1H, J = 5.2 Hz), 8.44 (t,1H, J =5.2 Hz), 10.75 (bs, 1H), 11.69 (s, 1H);m/z [M⁺ + 1] 321.1. 27

¹H NMR (DMSO-d₆) δ 3.28-3.36 (m, 4H), 7.70 (d, 1H, J = 5.2 Hz), 7.84 (d,1H, J = 5.2 Hz), 7.99 (s, 1H), 8.38(t, 1H, J = 5.2 Hz), 8.64-8.76 (m,2H), 11.20 (bs, 1H), 13.30 (s, 1H); m/z [M⁺ + 1] 497.9. 28

¹H NMR (DMSO-d₆) δ 2.91-2.98 (m, 2H), 3.32-3.25 (m, 2H), 7.26 (d, 1H, J= 4.8 Hz), 8.14 (t, 1H, J = 4.8 Hz), 8.79(d, 1H, J = 4.8 Hz), 10.53 (s,1H), 12.99 (s, 1H); m/z [M⁺ + 1] 482.9. 29

¹H NMR (DMSO-d₆) δ 2.84-2.88 (m, 2H), 3.32-3.40 (m, 2H), 8.84 (dd, 1H,J₁ = 5.6 Hz, J₂ = 8.4 Hz), 8.18-8.23 (m, 2H), 8.27 (d, 1H, J =4.8 Hz),8.60 (s, 1H), 13.05 (s, 1H); m/z [M⁺ + 1] 413.9. 30

¹H NMR (DMSO-d₆) δ 2.93-2.99 (m, 2H), 3.32-3.35 (m, 2H), 7.26-7.44 (m,1H), 7.65-7.82 (m, 1H), 8.27 (t, 1H, J = 5.6 Hz), 8.32 8.44 (m, 2H),11.10 (s, 1H), 13.19 (s, 1H), 13.76 (s, 1H); m/z [M⁺ + 1] 413.9. 31

¹H NMR (DMSO-d₆) δ 2.95-3.02 (m, 2H), 3.40-3.46 (m, 2H), 7.07 (s, 2H),7.29 (d, 2H, J =8.7 Hz), 7.31 (d, 1H, J = 1.6 Hz), 7.48 (d, 1H, J = 8.7Hz), 7.71 (d, 2H, J = 8.7 Hz), 8.41 (t, 1H, J = 5.3 Hz), 8.45 (d, 1H, J= 1.6 Hz), 9.68 (s, 1H), 11.99 (s, 1H); m/z [M⁺ + 1]418.0. 32

¹H NMR (DMSO-d₆) δ 3.07-3.12 (m, 2H), 3.42-3.48 (m, 2H), 7.36 (dd, 1H,J₁ = 2.4 Hz, J₂ =8.8 Hz), 7.39 (d, 1H, J = 5.6 Hz), 7.53 (d, 1H, J = 8.8Hz), 8.32 (d, 1H, J = 1.6 Hz), 8.44 (bs, 1H), 8.57 (t, 1H, J = 5.2 Hz),11.15 (s, 1H), 12.33 (s, 1H), 13.72 (s, 1H); m/z [M⁺ + 1] 340.1. 33

¹H NMR (DMSO-d₆) δ 2.98-3.04 (m, 2H), 3.40-3.44 (m, 2H), 7.32 (dd, 1H,J₁ = 1.6 Hz, J₂ = 8.8 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J₁ =5.2 Hz, J₂ = 8.8 Hz), 7.98 (d, 1H, J = 8.0 Hz), 8.22 (d, 1H, J = 5.2Hz), 8.35 (d, 1H, J = 1.6 Hz), 8.46 (t, 1H, J = 5.2 Hz), 8.51 (d, 2H, 3=2.0 Hz), 9.97 (s, 1H), 12.10 (s, 1H) m/z [M⁺ + 1] 340.1. 34

¹H NMR (DMSO-d₆) δ 2.90-2.96 (m, 2H), 3.35-3.39 (m, 2H), 7.08 (t, 1H, J= 6.8 Hz), 7.30 (t, 1H, J = 7.2 Hz), 7.40-7.46 (m, 4H), 7.91 (d, 2H, J =8.0 Hz), 8.06 (t, 1H, J = 8.0 Hz), 8.11 (t, 1H, J = 5.2 Hz), 8.14 (d,2H, J =6.0 Hz), 11.32 (bs, 1H), 12.05 (s, 1H); m/z [M⁺ + 1] 332.1. 35

¹H NMR (DMSO-d₆) δ 1.29 (d, 3H, J=6.4 Hz), 2.67 (dd, 1H, J₁ = 10.4 Hz,J₂ = 17.6 Hz), 3.09 (d, 1H, J = 17.6 Hz), 3.70-3.80 (m, 1H), 7.01 (t,1H, J = 2.4 Hz), 7.07 (t, 2H, J = 6.8 Hz), 7.38 (d, 1H, J = 8.8 Hz),7.88 (s, 1H), 8.02-8.12 (m, 2H), 11.39 (bs, 1H), 11.79 (s, 1H); m/z[M⁺ + 1] 270.1. 36

¹H NMR (DMSO-d₆) δ 2.90-2.96 (m, 2H), 3.32-3.10 (m, 2H), 7.01 (t, 1H, J= 6.8 Hz), 7.45 (d, 1H, J = 8.8 Hz), 7.97 (t, 1H, J = 7.2 Hz), 8.14 (d,1H, J = 6.0 Hz), 8.21 (t, 1H, J =5.2 Hz), 10.82 (bs, 1H), 13.14 (s, 1H);m/z [M⁺ + 1] 324.0. 37

¹H NMR (DMSO-d₆) δ 3.104-3.13 (m, 2H), 3.40-3.48 (m, 2H), 7.03 (t, 1H, J= 6.4 Hz), 7.19 (dt, 1H, J₁ = 2.8 Hz, J₂ = 8.8 Hz)), 7.40 (d, 1H, J =8.8 Hz), 7.50 (dd, 1H, J₁ = 5.2 Hz, J₂ = 8.8 Hz)), 8.00-8.06 (m, 2H),8.13 (d, 1H, J = 6.0 Hz), 8.50 (t, 1H, J = 6.0 Hz), 11.00 (bs, 1H),12.19 (s, 1H); m/z [M⁺ + 1] 324.1. 38

¹H NMR (DMSO-d₆) δ 1.32 (d, 3H, J = 6.4 Hz), 2.84 (dd, 1H, J₁ = 10.0 Hz,J₂ = 17.6 Hz), 3.24 (d, 1H, J = 17.6 Hz), 3.80-3.86 (m, 1H), 7.01 (t,1H, J = 6.8 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.40-7.48 (m, 2H), 7.99 (t,1H, J = 7.2 Hz), 8.13 (d, 1H, J = 5.8 Hz), 8.37 (d, 1H, J =3.6 Hz), 8.49(s, 1H), 10.84 (bs, 1H), 12.22 (s, 1H); m/z [M⁺ + 1] 398.0. 39

¹H NMR (DMSO-d₆) δ 2.90-3.02 (m, 2H), 3.41-3.43 (m, 2H), 7.05 (s, 1H),7.17 (t, 1H, J =8.0 Hz), 7.28 (d, 2H, J = 8.4 Hz), 7.44-7.50 (m, 1H),7.71 (d, 2H, J = 8.4 Hz), 8.09 (t, 1H, J = 8.8 Hz), 8.39 (s, 1H), 9.62(s, 1H), 11.90 (s, 1H); m/z [M⁺ + 1] 402.1. 40

¹H NMR (DMSO-d₆) δ 2.98-3.02 (m, 2H), 3.42-3.47 (m, 2H), 7.19 (t, 1H, J= 2.6 Hz), 7.49 (dd, 1H, J₁ =4.8 Hz, J₂ =8.9 Hz), 7.82 (dd, 1H, J₁ = 5.3Hz, J₂ = 8.6 Hz), 8.01 (d, 1H, J = 2.5 Hz), 8.04 (dd, 1H, J₁ = 2.5 Hz,J₂ =6.9 Hz), 8.24 (d, 1H, J = 5.1 Hz), 8.45 (t, 1H, J = 5.6 Hz), 8.53(d, 1H, # J = 2.5 Hz), 10.03 (s, 1H), 12.04 (s, 1H); m/z [M⁺ + 1]324.1.41

¹H NMR (DMSO-d₆) δ 2.89-2.96 (m, 2H), 3.38-3.45 (m, 2H), 6.82 (d, 1H, J= 8.8 Hz), 7.16 (dt, 1H, J₁ = 2.4 Hz, J₂ = 9.2 Hz), 7.46 (dd, 1H, J =4.8 Hz, J₂ = 8.8 Hz), 7.58 (dd, 1H, J₁ = 2.8 Hz, J₂ = 8.8 Hz), 8.07 (dd,1H, J₁ =2.0 Hz, J₂ = 10.4 Hz), 8.10 (d, 1H, J = 2.8 Hz), 8.37 (t, 1H, J= 5.6 Hz), # 9.04 (s, 1H), 11.84 (s, 1H); m/z [M⁺ = 1] 354.1. 42

¹H NMR (DMSO-d₆) δ 2.90-2.97 (m, 2H), 3.37-3.47 (m, 2H), 6.80 (d, 1H, J= 8.8 Hz), 7.29 (d, 1H, J = 8.8 Hz), 7.46 (d, 1H, J = 8.8 Hz), 7.57 (dd,1H, J₁ =2.8 Hz, J₂ = 8.8 Hz), 8.09 (s, 1H), 8.39 (t, 1H, J = 5.6 Hz),8.40 (s, 1H), 9.07 (s, 1H), 11.92 (s, 1H); m/z [M⁺ + 1]370.0. 43

¹H NMR (DMSO-d₆) δ 3.08-3.14 (m, 2H), 3.40-3.47 (m, 2H), 7.24-7.16 (m,1H), 7.44-7.52 (m, 2H), 7.83 (d, 1H, J = 8.0 Hz), 7.89 (d, 1H, J = 4.0Hz), 8.05 (dd, 1H, J₁ = 2.4 Hz, J₂ = 10.8 Hz), 8.26 (s, 1H), 8.47 (t,1H, J =4.8 Hz), 12.02 (s, 1H); m/z [M⁺ + 1] 358.0. 44

¹H NMR (DMSO-d₆) δ 3.06-3.16 (m, 2H), 3.40-3.46 (m, 2H), 7.32 (dd, 1H,J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.46 (dd, 1H, J₁ = 4.8 Hz, J₂ =8.4 Hz), 7.50(d, 1H, J = 8.4 Hz), 7.80 (dd, 1H, 3, 1.2 Hz, 12 6.4 Hz), 7.90 (dd, 1H,J₁ =1.2 Hz, J₂ = 4.4 Hz), 8.30 (s, 1H), 8.39 (d, 1H, J = 2 Hz), 8.49 (t,1H, J = 5.6 Hz), 12.10 (s, 1H); m/z [M⁺ + 1] 374.0. 45

¹H NMR (DMSO-d₆) δ 3.29-3.34 (m, 2H), 3.36-3.44 (m, 2H), 7.19 (d, 1H, J= 8.8 Hz), 7.30 (dd, 1H, J₁ =2.4 Hz, J₂ = 8.8 Hz), 7.48 (d, 1H, J = 8.0Hz), 7.83 (dd, 1H, J₁ = 2.4 Hz, J₂ = 8.8 Hz), 8.20 (d, 1H, J = 2.4 Hz),8.42 (t, 1H, J =5.6 Hz), 8.43 (s, 1H), 9.89 (s, 1H), 12.00 (s, 1H); m/z[M⁺ + 1] 374.0. 46

¹H NMR (DMSO-d₆) δ 2.98-3.03 (m, 2H), 3.36-3.42 (m, 2H), 7.17 (dt, 1H,J₁ = 2.4 Hz, J₂ = 9.2 Hz), 7.21 (d, 1H, J = 8.8 Hz), 7.48 (dd, 1H, J₁ =4.8 Hz, J₂ = 9.2 Hz), 7.84 (dd, 1H, J₁ = 2.8 Hz, J₂ = 8.8 Hz), 8.09 (dd,1H, J₁ =2.0 Hz, J₂ = 10.4 Hz), 8.20 (d, 1H, J = 2.0 Hz), 8.40 (t, 1H, J= 5.6 Hz), # 9.85 (s, 1H), 11.92 (s, 1H); m/z [M⁺ + 1] 358.1. 47

¹H NMR (DMSO-d₆) δ 3.02-3.07 (m, 2H), 3.40-3.44 (m, 2H), 7.25 (d, 1H, J= 8.8 Hz), 7.27 (s, 1H), 7.31(dd, 1H, J₁ = 2.0 Hz, J₂ =9.2 Hz), 7.49 (d,1H, J = 8.8 Hz), 8.06 (dd, 1H, J₁ =2.0 Hz, J₂ = 9.2 Hz), 8.44 (t, 1H, J=5.6 Hz), 8.48 (s, 1H), 8.56 (d, 1H, J = 2.0 Hz), 10.34 (s, 1H), 12.06(s, 1H); m/z [M⁺ + 1]419.1. 48

¹H NMR (DMSO-d₆) δ 3.02-3.07 (m, 2H), 3.41-3.44 (m, 2H), 7.17 (dt, 1H,J₁ = 2.8 Hz, J₂ = 9.2 Hz), 7.25-7.30 (m, 3H), 7.49(dd, 1H, J₁ =4.8 Hz,J₂ = 8.8 Hz), 8.07 (dd, 1H, J₁ =2.0 Hz, J₂ = 8.8 Hz), 8.13 (dd, 1H, J₁ =2.0 Hz, J₂ = 10.4 Hz), 8.42 (t, 1H, J = 5.6 Hz), 8.56 (d, 1H, J = 2.4Hz), 10.27 # (s, 1H), 11.98(s, 1H); m/z [M⁺ + 1] 403.1. 49

¹H NMR (DMSO-d₆) δ 3.02-3.08 (m, 2H), 3.37-3.42 (m, 2H), 7.18 (dt, 1H,J₁ = 2.8 Hz, J₂ = 8.8 Hz), 7.30(d, 1H, J = 8.8 Hz), 7.49 (dd, 1H, J₁ =4.8 Hz, J₂ =8.8 Hz), 8.06-8.13 (2H, m), 8.44 (t, 1H, J = 5.6 Hz), 8.52(s, 1H), 10.27 (s, 1H), 12.00 (s, 1H); m/z [M⁺ + 1]392.1. 50

¹H NMR (DMSO-d₆) δ 3.02-3.08 (m, 2H), 3.36-3.42 (m, 2H), 7.28 (d, 1H, J= 9.0 Hz), 7.31(dd, 1H, J₁ = 2.0 Hz, J₂ = 9.0 Hz), 7.49 (d, 1H, J = 8.0Hz), 8.07 (dd, 1H, J₁ = 2.8 Hz, J₂ = 9.0 Hz), 8.44-8.49 (m, 2H), 8.53(s, 1H), 10.35 (s, 1H), 12.08 (s, 1H); m/z [M⁺ + 1]408.1. 51

¹H NMR (DMSO-d₆) δ 3.06-3.11 (m, 2H), 3.38-3.42 (m, 2H), 7.22 (d, 1H, J= 9.6 Hz), 7.33 (dd, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.50 (d, 1H, J = 8.4Hz), 8.43-8.53 (m, 3H), 9.07 (d, 1H, J = 2.8 Hz), 10.91 (s, 1H), 12.17(s, 1H); m/z [M⁺ + 1] 385.0. 52

¹H NMR (DMSO-d₆) δ 2.93-2.98 (m, 2H), 3.42-3.44 (m, 2H), 7.31 (dd, 1H,J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.39 (d, 1H, J = 8.8 Hz), 7.48 (d, 1H, J =8.8 Hz), 7.57 (dd, 1H, J₁ = 3.2 Hz, J₂ =8.8 Hz), 8.31 (d, 1H, J = 2.8Hz), 8.36 (d, 1H, J = 1.6 Hz), 8.41 (t, 1H, J = 5.6 Hz), 9.52 (s, 1H),12.00 (s, 1H); m/z [M⁺ + 1] 374.0. 53

¹H NMR (DMSO-d₆) δ 3.43 2H, J = 6.0 Hz), 3.91 (s, 2H), 5.97 (t, 1H, J =7.6 Hz), 7.08 (t, 1H, J = 8.0 Hz), 7.24 (t, 2H, J = 7.2 Hz), 7.47(d, 1H,J = 8.0 Hz), 7.57 (dd, 1H, J₁ =5.2 Hz, J₂ = 8.0 Hz), 7.90 (d, 1H, J =8.0 Hz), 8.12-8.17 (m, 2H), 8.36 (d, 1H, J = 5.2 Hz), 8.88 (s, 1H),10.62 (s, 1H), 11.92 (s, 1H); m/z [M⁺ + 1] 333.1. 54

¹H NMR (DMSO-d₆) δ 3.44 (t, 2H, J = 6.0 Hz), 4.02 (s, 2H), 5.97 (t, 1H,J = 7.2 Hz), 7.07 (t, 1H, J = 7.2 Hz), 7.24 (t, 2H, J = 7.2 Hz), 7.47(d,1H, J = 8.0 Hz), 7.84 (d, 1H, J =8.0 Hz), 7.93 (d, 2H, J = 6.4 Hz), 8.16(t, 1H, J = 5.2 Hz), 8.62 (d, 2H, J = 6.4 Hz), 11.40 (s, 1H), 11.95 (s,1H); m/z [M⁺ + 1] 333.1. 55

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.8 Hz), 3.87 (s, 2H), 5.97 (t, 1H,J = 7.6 Hz), 7.08 (t, 1H, J = 6.4 Hz), 7.16-7.21 (bs, 1H), 7.24 (t, 1H,J = 7.2 Hz), 7.47(d, 1H, J = 8.8 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.79 (d,2H, J =8.8 Hz), 7.80-7.83 (m, 1H), 7.91 (d, 1H, J =8.0 Hz), 8.13 (t, 1H,J = 5.2 Hz), 10.29 (s, 1H), 11.91 (s, 1H); m/z (M⁺ + 1] 375.1. 56

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.0 Hz), 3.88 (s, 2H), 5.97 (t, 1H,J = 6.8 Hz), 7.08 (t, 1H, J = 7.2 Hz), 7.19-7.26 (m, 3H), 7.47 (d, 1H, J= 8.0 Hz), 7.67-7.74 (m, 4H), 7.90 (d, 1H, J = 8.0 Hz), 8.13 (t, 1H, J =4.8 Hz), 10.43 (s, 1H), 11.91 (s, 1H); m/z [M⁺ + 1]411.0. 57

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.8 Hz), 3.87 (s, 2H), (m, 2H), 5.96(t, 1H, J = 7.2 Hz), 7.08 (t, 1H, J = 6.4 Hz), 7.24 (t, 1H, J =7.2 Hz),7.31 (s, 2H), 7.45-7.49 (m, 3H), 7.66-7.72 (m, 1H), 7.92 (d, 1H, J = 8.0Hz), 8.12-8.16 (m, 2H), 10.40 (s, 1H), 11.91 (s, 1H); m/z [M⁺ + 1]411.0. 58

¹H NMR (DMSO-d₆) δ 3.47 (t, 2H, J = 6.0 Hz), 3.89 (s, 2H), 6.09 (t, 1H,J = 7.6 Hz), 7.09 (t, 1H, J = 7.6 Hz), 7.25 (t, 2H, J = 7.6 Hz),7.46-7.59 (m, 4H), 7.79-7.84 (m, 2H), 8.11-8.16 (m, 2H), 9.61 (s, 1H),11.95 (s, 1H); m/z [M⁺ + 1] 411.0. 59

¹H NMR (DMSO-d₆) δ 1.14-1.38 (m, 4H), 1.58-1.70 (m, 2H), 1.90-1.98 (m,1H), 2.78-2.88 (m, 1H), 3.43 (t, 2H, J = 6.0 Hz), 3.54-3.72 (m, 4H),5.89 (t, 1H, J = 6.4 Hz), 7.08 (t, 1H, J = 8.0 Hz), 7.25 (t, 2H, J = 7.2Hz), 7.77 (bs, 3H), 7.86 (d, 1H, J = 8.0 Hz), 7.99 (d, 1H, J = 8.8 Hz),8.13 (t, 1H, J = 4.8 Hz), 11.89 (s, 1H); m/z [M⁺ + 1] 353.2. 60

¹H NMR (DMSO-d₆) δ 1.10-1.38 (m, 4H), 1.69-1.77 (m, 2H), 1.84-1.92 (m,2H), 2.90-3.00 (m, 1H), 3.36 (t, 2H, J = 6.0 Hz), 3.38-3.42 (m, 1H),3.55 (s, 2H), 5.85 (t, 1H, J = 6.4 Hz), 7.06 (t, 1H, J = 7.2 Hz), 7.24(t, 1H, J =8.0 Hz), 7.45 (d, 1H, J = 8.0 Hz), 7.76 (bs, 3H), 7.86 (d,1H, J = 8.0 Hz), 8.11 (t, 1H, J =5.2 Hz), 11.86 (s, 1H); m/z [M⁺ + 1]353.2. 61

¹H NMR (DMSO-d₆) δ 1.08-1.18 (m, 4H), 1.60-1.68 (m, 2H), 1.72-1.80 (m,2H), 3.36-3.42 (m, 4H), 3.53 (s, 2H), 5.85 (t, 1H, J = 7.6 Hz), 7.06 (t,1H, J = 7.2 Hz), 7.24 (t, 1H, J =8.0 Hz), 7.73 (d, 1H, J = 8.4 Hz), 7.86(d, 1H, J = 8.4 Hz), 8.10 (t, 1H, J = 5.2 Hz), 11.86 (s, 1H); m/z [M⁺ +1] 354.1. 62

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.0 Hz), 3.73 (s, 2H), 4.38 (d, 2H,J = 5.6 Hz), 5.95 (t, 1H, J = 7.2 Hz), 7.07 (t, 1H, J = 8.0 Hz), 7.26(t, 1H, J = 8.0 Hz), 7.38 (d, 2H, J =6.0 Hz), 7.48 (d, 1H, J = 8.0 Hz),7.88 (d, 1H, J = 8.0 Hz), 8.16 (t, 1H, J = 5.2 Hz), 8.57 (d, 2H, J = 6.0Hz), 8.59 (t, 1H, J = 6.0 Hz), 11.91 (s, 1H); m/z [M⁺ + 1] 347.1. 63

¹H NMR (DMSO-d₆) δ 3.44 (t, 2H, J = 6.4 Hz), 3.99 (s, 2H), 6.02 (t, 1H,J = 6.4 Hz), 7.09 (t, 1H, J = 8.8 Hz), 7.25 (t, 1H, J = 7.2 Hz), 7.37(dd, 1H, J₁ = 3.6 Hz, J₂ = 8.8 Hz), 7.47 (d, 1H, J = 8.8 Hz), 7.95 (d,1H, J = 8.0 Hz), 8.08-8.18 (m, 3H), 9.58 (s, 1H), 11.93 (s, 1H); m/z[M⁺ + 1] 367.0. 64

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.0 Hz), 3.84 (s, 2H), 5.95 (t, 1H,J = 7.6 Hz), 7.08 (t, 1H, J = 7.6 Hz), 7.24 (t, 1H, J = 6.4 Hz), 7.42(d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J =8.8 Hz), 7.88 (d, 1H, J = 8.0 Hz),8.01(dd, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 8.14 (t, 1H, J =2.8 Hz), 8.54(d, 1H, J = 2.8 Hz), 10.47 (s, 1H), 11.92 (s, 1H); m/z [M⁺ + 1] 367.0.65

¹H NMR (DMSO-d₆) δ 3.44 (t, 2H, J = 6.4 Hz), 3.96 (s, 2H), 6.01 (t, 1H,J = 6.4 Hz), 7.12 (dt, 1H, J₁ = 2.0 Hz, J₂ = 9.6 Hz), 7.37 (dd, 1H, J₁ =4.2 Hz, J₂ = 8.0 Hz), 7.46 (dd, 1H, J₁ = 4.4 Hz, J₂ = 9.6 Hz), 7.75 (dd,1H, J₁ =2.4 Hz, J₂ = 10.0 Hz), 8.08 (dd, 1H, J₁ = # Hz, J₂ = 8.0 Hz),8.14 (dd, 1H, J₂ = 2.0 Hz, J₂ =4.4 Hz), 8.21 (t, 1H, J = 5.6 Hz), 9.63(s, 1H), 12.04 (s, 1H); m/z [M⁺ + 1] 385.0. 66

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.4 Hz), 3.83 (s, 2H), 5.97 (t, 1H,J = 6.4 Hz), 7.12 (dt, 1H, J₁ = 2.4 Hz, J₂ = 8.8 Hz), 7.30 (s, 2H),7.44-7.50 (m, 3H), 7.66-7.74 (m, 2H), 8.14 (s, 1H), 8.19 (t, 1H, J = 5.6Hz), 10.41 (s, 1H), 12.03 (s, 1H); m/z [M⁺ + 1] 429.0. 67

¹H NMR (DMSO-d₆) δ 3.42 (t, 2H, J = 6.4 Hz), 3.69 (s, 2H), 4.39 (d, 2H,J = 5.6 Hz), 5.96 (t, 1H, J = 6.4 Hz), 7.13 (dt, 1H, J₁ = 2.4 Hz, J₂ =8.8 Hz), 7.41 (d, 2H, J = 6.8 Hz), 7.47 (dd, 1H, J₁ = 5.2 Hz, J₂ = 8.8Hz), 7.66 (dd, 1H, J₁ = 2.0 Hz, J₂ = 10.8 Hz), 8.21 (t, 1H, J = 6.0 Hz),8.58 (d, 2H, J = # 6.8 Hz), 8.63 (t, 1H, J = 5.6 Hz), 12.03 (s, 1H); m/z[M⁺ + 1]365.1. 68

¹H NMR (DMSO-d₆) δ 3.44 (t, 2H, J = 6.0 Hz), 3.99 (s, 2H), 5.97 (t, 1H,J = 6.0 Hz), 7.12 (dt, 1H, J₁ = 2.4 Hz, J₂ = 9.6 Hz), 7.47 (dd, 1H, J₁ =5.2 Hz, J₂ = 8.4 Hz), 7.63 (dd, 1H, J₁ = 2.4 Hz, J₂ = 11.2 Hz), 7.93 (d,2H, J =6.8 Hz), 8.22 (t, 1H, J = 4.4 Hz), 8.62 (d, 2H, J = 6.8 Hz),11.38 (s, 1H), 12.07 # (s, 1H); m/z [M⁺ + 1] 351.1. 69

¹H NMR (DMSO-d₆) δ 0.77 (t, 3H, J= 8.0 Hz), 1.34 (sextet, 2H, J = 7.6Hz), 2.97 (q, 2H, J = 6.0 Hz), 3.39 (t, 2H, J = 6.0 Hz), 3.52 (s, 2H),5.88 (t, 1H, J = 7.2 Hz), 7.11 (dt, 1H, J₁ = 6.0 Hz, J₂ = 8.8 Hz), 7.45(dd, 1H, J₁ =4.8 Hz, J₂ = 9.2 Hz), 7.66 (dd, 1H, J₁ = 2.8 Hz, J₂ = 10.8Hz), 7.91 (t, 1H, J = # 6.0 Hz), 8.16 (t, 1H, J = 5.2 Hz), 11.97 (s,1H); m/z [M⁺ + 1] 316.1. 70

¹H NMR(DMSO-d₆)δ 2.76-2.82(m, 2H), 3.25(q, 2H, J=6.0 Hz), 3.41(t, 2H,J=6.8 Hz), 3.56(s, 2H), 5.90(t, 1H, J=7.2 Hz), 7.13(dt, 1H, J₁=2.4 Hz,J₂=8.8 Hz), 7.46 (dd, 1H, J₁=5.2 Hz, J₂=8.8 Hz), 7.62(dd, 1H, J₁=2.4 Hz,J₂=11.2 Hz), 7.66-7.72(bs, 3H), 8.16(t, 1H, J=5.2 Hz), 8.19 (t, 1H,J=5.2 Hz), 12.01(s, 1H); m/z [M⁺ + 1] 317.0. 71

¹H NMR (DMSO-d₆) δ 3.10 (q, 2H, J = 6.0 Hz), 3.35 (t, 2H, J = 6.0 Hz),3.93 (t, 2H, J =6.4 Hz), 3.53 (s, 2H), 5.89 (t, 1H, J = 6.8 Hz), 7.12(dt, 1H, J₁ = 2.4 Hz, J₂ =8.8 Hz), 7.46 (dd, 1H, J₁ = 5.2 Hz, J₂ = 9.6Hz), 7.66 (dd, 1H, J₁ = 1.6 Hz, J₂ = 10.8 Hz), 7.96 (t, 1H, J =5.6 Hz),8.16 (t, 1H, J = 4.8 Hz), 11.98 # (s, 1H); m/z [M⁺ + 1] 318.1. 72

¹H NMR(DMSO-d₆)δ 1.49(quint, 2H, J=6.8 Hz), 3.08(q, 2H, J=5.6 Hz),3.35(t, 2H, J=6.4 Hz), 3.40(t, 2H, J=6.0 Hz), 3.51(s, 2H), 5.88(t, 1H,J=6.8 Hz), 7.12(dt, 1H, J₁=2.8 Hz, J₂=8.8 Hz), 7.45(dd, 1H, J₁=5.2 Hz,J₂=8.8 Hz), 7.66(dd, 1H, J₁=2.4 Hz, J₂=11.2 Hz), 7.93(t, 1H, J=5.6 Hz),8.16(t, 1H, J=5.2 Hz), 11.98(s, 1H); m/z[M⁺ + 1] 332.1. 73

¹H NMR(DMSO-d₆)δ 2.54(s, 6H), 3.06(t, 2H, J=6.4 Hz), 3.37(t, 2H, J=7.2Hz), 3.41 (t, 2H, J=6.4 Hz), 3.58(s, 2H), 5.91(t, 1H, J=7.2 Hz),7.13(dt, 1H, J₁=3.2 Hz, J₂=8.8 Hz), 7.46(dd, 1H, J₁=5.2 Hz, J₂=9.6 Hz),7.63(dd, 1H, J₁=2.4 Hz, J₂=10.4 Hz), 8.19 (t, 1H, J=5.2 Hz), 8.22(t, 1H,J=5.6 Hz), 9.34(bs, 1H), 12.02(s, 1H); m/z[M⁺ + 1] 345.1. 74

¹H NMR (DMSO-d₆) δ 2.81 & 3.01 (s, 3H), 3.20 & 3.26 (s, 3H), 3.33-3.44(m, 4H), 3.46-3.51 (m, 2H), 3.77 & 3.81(s, 2H), 5.74 & 5.76 (t, 1H, J =6.4 Hz), 7.11 (d, 1H, J = 9.2 Hz), 7.44-7.52 (m, 2H), 8.15 & 8.16 (t,1H, J = 5.6 Hz), 11.97 & 11.99 (s, 1H); m/z [M⁺ + 1]346.16. 75

¹H NMR (DMSO-d₆) δ 3.38-3.57 (m, 10H), 3.81 (s, 2H), 5.78 (t, 1H, J =6.8 Hz), 7.12 (dt, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.46 (dd, 1H, J₁ =4.4Hz, J₂ = 8.8 Hz), 7.56 (dd, 1H, J₁ = 2.4 Hz, J₂ = 10.8 Hz), 8.17 (t, 1H,J = 5.2 Hz), 12.00 (s, 1H); m/z [M⁺ + 1] 344.1. 76

¹H NMR (DMSO-d₆) δ 3.48 (t, 2H, J = 6.4 Hz), 3.88 (s, 2H), 6.08 (t, 1H,J = 6.4 Hz), 7.13 (tt, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.26 (dt, 1H, J₁ =2.4 Hz, J₂ = 7.2 Hz), 7.46-7.51 (m, 1H), 7.51-7.57 (m, 1H), 7.57 (s,2H), 7.63(dt, 1H, J₁ = 2.4 Hz, J₂ = 10.8 Hz), 7.82 (dt, 1H, J₁ +321 2.0Hz, J₂ = 8.0 Hz), # 8.08 (dd, 1H, J₁ = 1.6 Hz, J₂ = 8.0 Hz), 8.19 (t,1H, J =6.0 Hz), 9.59 (s, 1H), 12.07 (s, 1H); m/z [M⁺ + 1] 429.0. 77

¹H NMR (DMSO-d₆) δ 3.00-3.20 (m, 2H), 3.38-3.50 (m, 6H), 3.60-3.70 (m,2H), 3.88 (s, 2H), 5.78 (t, 1H, J = 6.4 Hz), 7.13 (dt, 1H, J₁ =1.6 Hz,J₂ = 8.8 Hz), 7.46 (dd, 1H, J₁ = 5.2 Hz, J₂ = 9.2 Hz), 7.57 (dd, 1H, J₁= 2.4 Hz, J₂ =10.0 Hz), 8.18 (t, 1H, J = 5.2 Hz), 12.02 (s, 1H); m/z[M⁺ + 1] 343.1. 78

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.8 Hz), 3.84 (s, 2H), 5.96 (t, 1H,J = 6.4 Hz), 7.12 (dt, 1H, J₁ = 2.8 Hz, J₂ = 8.4 Hz), 7.20 (s, 2H),7.44-7.50 (m, 1H), 7.68-7.76 (m, 5H), 8.18 (t, 1H, J = 5.2 Hz), 10.44(s, 1H), 12.02 (s, 1H) m/z [M⁺ + 1] 429.0. 79

¹H NMR (DMSO-d₆) δ 3.42 (t, 2H, J = 6.0 Hz), 3.91 (s, 2H), 5.96 (t, 1H,J = 7.6 Hz), 7.07-7.13 (m, 2H), 7.45 (dt, 1H, J₁ = 4.4 Hz, J₂ = 8.8 Hz),7.72-7.78 (m, 2H), 7.94 (d, 1H, J =8.8 Hz), 8.18 (t, 1H, J = 5.2 Hz),8.29 (d, 1H, J = 5.2 Hz), 10.70 (s, 1H), 12.01 (s, 1H); m/z [M⁺ + 1]351.1. 80

¹H NMR (DMSO-d₆) δ 3.44 (t, 2H, J = 6.0 Hz), 3.88 (s, 2H), 5.98 (t, 1H,J = 6.4 Hz), 7.12 (dt, 1H, J₁ = 2.4 Hz, J₂ = 9.6 Hz), 7.47 (dd, 1H, J₁ =5.2 Hz, J₂ = 8.8 Hz), 7.60 (dd, 1H, J₁ = 4.4 Hz, J₂ = 8.4 Hz), 7.68 (d,1H, J =8.8 Hz), 8.16 (d, 1H, J = 9.6 Hz), 8.19 (t, 1H, J = 5.2 Hz), 8.39(d, 1H, J = 5.2 Hz), # 8.91 (s, 1H), 10.64 (s, 1H), 12.04 (s, 1H); m/z[M⁺ + 1]351.1. 81

¹H NMR (DMSO-d₆) δ 3.43 (t, 2H, J = 6.4 Hz), 3.83 (s, 2H), 5.96 (t, 1H,J = 6.4 Hz), 7.12 (dt, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.18(bs, 1H), 7.46(dd, 1H, J₁ = 4.4 Hz, J₂ =8.8 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.70 (d,1H, J = 10.8 Hz), 7.80 (d, 2H, J = 8.8 Hz), 8.18 (t, 1H, J = 5.2 Hz),10.30 (s, 1H), 12.02 (s, 1H); m/z [M⁺ + 1] 393.1. 82

¹H NMR (DMSO-d₆) δ 1.13-1.38 (m, 4H), 1.57-1.70 (m, 2H), 1.92-1.98 (m,1H), 2.80-2.90 (m, 1H), 3.41 (t, 2H, J = 6.4 Hz), 3.50-3.68 (m, 4H),5.89 (t, 1H, J = 7.2 Hz), 7.12 (dt, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.46(dd, 1H, J₁ = 4.4 Hz, J₂ = 8.8 Hz), 7.66 (dd, 1H, J₁ =2.0 Hz, J₂ = 11.2Hz), 7.79 (bs, 3H), # 8.02(d 1H, J = 8.8 Hz), 8.18 (t, 1H, J = 5.2 Hz),11.99 (s, 1H); m/z [M⁺ + 1] 371.1. 83

¹H NMR (DMSO-d₆) δ 2.72-2.79 (m, 2H), 3.33-3.37 (m, 2H), 7.07-7.19 (m,2H), 7.22 (s, 2H), 7.42-7.48 (m, 2H), 7.63 (d, 2H, J = 8.8 Hz), 7.73 (d,2H, J = 8.8 Hz), 8.19 (t, 1H, J =4.8 Hz), 8.47 (d, 1H, J = 11.2 Hz),9.23 (s, 1H), 11.66 (s, 1H); m/z [M⁺ + 1] 444.0. 84

¹H NMR (DMSO-d₆) δ 2.72-2.79 (m, 2H), 3.32-3.38 (m, 2H), 7.13 (dt, 1H,J₁ = 2.8 Hz, J₂ = 8.8 Hz), 7.18 (d, 1H, J = 10.0 Hz), 7.35 (s, 2H),7.42-7.49 (m, 4H), 7.54 (d, 1H, J =8.4 Hz), 8.10 (s, 1H), 8.18 (t, 1H, J= 5.2 Hz), 8.39 (d, 1H, J = 10.0 Hz), 9.18 (s, 1H), 11.65 (s, 1H); m/z[M⁺ + 1] 444.0. 85

¹H NMR (DMSO-d₆) δ 0.88 (t, 3H, J = 6.8 Hz), 1.44 (q, 2H, J = 6.8 Hz),2.64-2.68 (m, 2H), 3.06 (q, 2H, J = 6.4 Hz), 3.27-3.33 (m, 2H), 6.37 (t,1H, J = 5.2 Hz), 7.09 (dd, 1H, J₁ =2.8 Hz, J₂ = 9.6 Hz), 7.13 (d, 1H, J= 10.4 Hz), 7.37-7.43 (m, 2H), 8.06 (d, 1H, J = 11.2 Hz), 8.11 (t, 1H, J= 5.2 Hz), 11.54 (s, 1H); m/z [M⁺ + 1] 331.1. 86

¹H NMR (DMSO-d₆) δ 2.75-2.80 (m, 2H), 3.30-3.34 (m, 2H), 7.10-7.17 (m,2H), 7.44-7.49 (m, 2H), 7.90-7.96 (bs, 2H), 8.22 (t, 1H, J = 5.2 Hz),8.59-8.68 (bs, 2H), 9.11 (d, 1H, J =10.4 Hz), 10.62 (s, 1H), 11.74 (s,1H); m/z [M⁺ + 1] 366.1. 87

¹H NMR(DMSO-d₆)δ 2.73-2.78(m, 2H), 3.32-3.36(m, 2H), 7.10-7.16(m, 2H),7.31 (dd, 1H, J₁=1.6 Hz, J₂=5.2 Hz), 7.42-7.47 (m, 2H), 7.70(s, 1H),8.19(d, 2H, J=6.0 Hz), 8.65(d, 1H, J=10.8 Hz), 9.54(s, 1H), 11.69(s,1H); m/z[M⁺ + 1] 400.0. 88

¹H NMR (DMSO-d₆) δ 2.78-2.82 (m, 2H), 3.35-3.40 (m, 2H), 7.03 (dd, 1H,J₁ = 5.6 Hz, J₂ = 7.2 Hz), 7.13 (dt, 1H, J₁ = 2.8 Hz, J₂ =9.6 Hz), 7.23(d, 1H, J = 10.8 Hz), 7.43-7.48 (m, 3H), 7.77 (dt, 1H, J₁ = 2.0 Hz, J₂ =7.8 Hz), 8.21 (t, 1H, J = 5.2 Hz), 8.31 (d, 1H, J =5.2Hz), 9.73 (s, 1H),10.39 (bs, 1H), # 11.67 (s, 1H); m/z [M⁺ + 1] 366.1. 89

¹H NMR (DMSO-d₆) δ 2.70-2.75 (m, 2H), 3.30-3.36 (m, 2H), 6.84 (d, 1H, J= 2.8 Hz), 7.10-7.15 (m, 2H), 7.43-7.46 (m, 2H), 8.19 (t, 1H, J = 5.6Hz), 8.54 (d, 1H, J = 10.8 Hz), 8.75(d, 1H, J = 2.0 Hz), 9.74 (s, 1H),11.68 (s, 1H); m/z [M⁺ + 1] 356.1. 90

¹H NMR (DMSO-d₆) δ 2.73-2.76 (m, 2H), 3.33-3.37 (m, 2H), 7.11-7.16 (m,3H), 7.38 (d, 1H, J = 3.6 Hz), 7.43-7.48 (m, 2H), 8.19 (t, 1H, J = 5.2Hz), 8.67 (d, 1H, J = 10.4 Hz), 10.60 (bs, 1H), 11.69 (s, 1H); m/z [M⁺ +1]372.0. 91

¹H NMR (DMSO-d₆) δ 1.18-1.28 (m, 2H), 1.34-1.44 (m, 2H), 1.88-1.98 (m,4H), 2.52-2.54 (m, 1H), 2.62-2.68 (m, 2H), 2.97-3.04 (m, 1H), 3.28-3.32(m, 2H), 6.39 (d, 1H, J =7.2 Hz), 7.07-7.14 (m, 2H), 7.36-7.43 (m, 2H),7.80 (s, 3H), 8.07 (d, 1H, J = 10.4 Hz), 8.11 (t, 1H,J 5.2 Hz), 11.54(s, 1H); m/z [M⁺ + 1] 386.3. 92

¹H NMR (DMSO-d₆) δ 1.58 (quint, 2H, J =6.4 Hz), 2.63-2.68 (m, 2H), 3.17(q, 2H, J =6.4 Hz), 3.28-3.33 (m, 2H), 3.45 (t, 2H, J =6.4 Hz), 6.37 (t,1H, J = 8.8 Hz), 7.09 (dd, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.13 (d, 1H, J=9.6 Hz), 7.38-7.43 (m, 2H), 8.10 (d, 1H, J =3.6 Hz), 8.13 (s, 1H),11.53 (s, 1H); m/z [M⁺ + 1] 347.1. 93

¹H NMR (DMSO-d₆) δ 2.67-2.70 (m, 2H), 2.83 (d, 6H, J = 5.2 Hz), 3.18 (q,2H, J = 5.2 Hz), 3.28-3.33 (m, 2H), 3.47 (q, 2H, J = 5.2 Hz), 6.71 (t,1H, J = 5.6 Hz), 7.08-7.15 (m, 2H), 7.38-7.44 (m, 2H), 8.15 (t, 1H, J =5.2 Hz), 8.45 (d, 1H, J = 10.4 Hz), 9.34 (bs, 1H), 11.59 (s, 1H); rn/z[M⁺ + 1] 360.2. 94

¹H NMR (DMSO-d₆) δ 2.64-2.68 (m, 2H), 3.17 (q, 2H, J = 6.0 Hz),3.28-3.33 (m, 2H), 3.45 (t, 2H, J = 5.4 Hz), 6.49 (t, 1H, J = 5.6 Hz),7.10 (dt, 1H, J₁ = 2.8 Hz, J₂ = 8.8 Hz), 7.13 (d, 1H, J = 9.6 Hz),7.37-7.43 (m, 2H), 8.12 (t, 1H, J = 5.6 Hz), 8.21 (d, 1H, J = 10.8 Hz),11.54 (s, 1H); m/z [M⁺ + 1] 333.1. 95

¹H NMR (DMSO-d₆) δ 2.66-2.70 (m, 2H), 2.91 (q, 2H, J = 6.0 Hz),3.28-3.32 (m, 2H), 3.34 (t, 2H, J = 6.0 Hz), 6.65 (t, 1H, J = 5.2 Hz),7.08-7.15 (m, 2H), 7.39-7.44 (m, 2H), 7.76 (bs, 3H), 8.14 (t, 1H, J =5.2 Hz), 8.40 (d, 1H, J = 10.8 Hz), 11.59 (s, 1H); m/z [M⁺ + 1] 332.0.96

¹H NMR (DMSO-d₆) δ 2.7 1-2.73 (m, 2H), 3.30-3.34 (m, 2H), 4.55 (d, 2H, J= 6.0 Hz), 7.07-7.19 (m, 3H), 7.37-7.44 (m, 2H), 7.77 (d, 2H, J = 6.4Hz), 8.14 (t, 1H, J = 5.2 Hz), 8.54 (d, 1H, J = 10.0 Hz), 8.77 (d, 2H, J= 5.2 Hz), 11.57 (s, 1H); m/z [M⁺ + 1] 380.0. 97

¹H NMR (DMSO-d₆) δ 2.62-2.67 (m, 2H), 2.92 (t, 2H, J = 6.4 Hz), 3.27-3.31 (m, 2H), 3.44 (q, 2H, J = 6.4 Hz), 6.49 (t, 1H, J = 5.2 Hz), 7.07-7.13(m, 2H), 7.38 (dd, 1H, J₁ = 2.0 Hz, J₂ = 10.0 Hz), 7.41 (dd, 1H, J₁ =4.4 Hz, J₂ = 8.8 Hz), 7.80 (dd, 1H, J₁ = 5.2 Hz, J₂ =8.8 Hz), 8.12 (t,1H, J = 4.4 Hz), # 8.17 (d, 1H, J = 10.8 Hz), 8.21 (d, 1H, J = 8.0 Hz),8.68 (d, 1H, J = 5.2 Hz), 8.71 (s, 1H), 11.56 (s, 1H); m/z [M⁺ + 1]394.2. 98

¹H NMR (DMSO-d₆) δ 2.60-2.66 (m, 2H), 3.10 (t, 2H, J = 6.4 Hz),3.26-3.31 (m, 2H), 3.55 (q, 2H = 6.4 Hz), 6.55 (t, 1H, J = 5.2 Hz), 7.06(d, 1H, J = 10.8 Hz), 7.10 (dt, 1H, J₁ = 1.6 Hz, J₂ = 8.8 Hz), 7.37 (dd,1H, J₁ =2.4 Hz, J₂ = 10.8 Hz), 7.41 (dd, 1H, J₁ = 4.8 Hz, J₂ = 8.8 Hz),7.70 (t, 1H, J = # 6.8 Hz), 7.75(d, 1H, J = 7.6 Hz), 8.12 (t, 1H, J =5.2 Hz), 8.19 (d, 1H, J = 10.8 Hz), 8.27 (t, 1H, J =7.6 Hz), 8.75 (d,1H, J = 5.2 Hz), 11.56 (s, 1H); m/z [M⁺ + 1] 394.2. 99

¹H NMR (DMSO-d₆) δ 1.20-1.40 (m, 4H), 1.66-1.72 (m, 2H), 1.82-1.88 (m,1H), 1.92-2.00 (m, 1H), 2.65-2.70 (m, 2H), 2.84-2.92 (m, 1H), 3.29-3.33(m, 2H), 3.52-3.58 (m, 1H), 6.63 (d, 1H, J = 8.0 Hz), 7.10 (dt, 1H, J₁=2.0 Hz, J₂ = 9.6 Hz), 7.15 (d, 1H, J = 10.8 Hz), 7.40-7.45 (m, 2H),7.81 (bs, 3H), 8.14 (t, 1H, J = 4.8 Hz), 8.34 (d, 1H, J = # 11.2 Hz),11.58 (s, 1H); m/z [M⁺ + 1] 386.2. 100

¹H NMR (DMSO-d₆) δ 1.61 (quint, 2H, J =6.4 Hz), 3.18 (q, 2H, J = 6.4Hz), 3.23-3.28 (m, 2H), 3.42-3.48 (m, 2H), 3.45 (t, 2H, J =6.4 Hz), 6.35(s, 1H), 7.16 (dt, 1H, J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.48 (dd, 1H, J₁ = 4.2Hz, J₂ =8.8 Hz), 7.76 (dd, 1H, J₁ = 2.0 Hz, J₂ = 10.0 Hz), 8.16 (t, 1H,J = 4.8 Hz), 8.36 (t, 1H, # J = 5.2 Hz), 12.03 (s, 1H); m/z [M⁺ + 1]332.1. 101

¹H NMR (DMSO-d₆) δ 3.21 (q, 2H, J = 6.0 Hz), 3.24-3.28 (m, 2H),3.43-3.45 (m, 2H), 3.46 (t, 2H, J = 6.0 Hz), 6.39 (s, 1H), 7.16 (dt, 1H,J₁ = 2.0 Hz, J₂ = 9.6 Hz), 7.49 (dd, 1H, J₁ =5.2 Hz, J₂ = 8.8 Hz), 7.79(dd, 1H, J₁ = 2.0 Hz, J₂ = 10.8 Hz), 8.25 (t, 1H, J = 5.6 Hz), 8.36 (t,1H, J = 4.8 Hz), 12.02 (s, 1H); # [M⁺ + 1] 318.1. 102

¹H NMR (DMSO-d₆) δ 2.88-2.96 (m, 2H), 3.24-3.29 (m, 2H), 3.37 (q, 2H, J= 6.0 Hz), 3.43-3.47 (m, 2H), 6.34 (s, 1H), 7.17 (dt, 1H, J₁ = 2.0 Hz,J₂ = 9.2 Hz), 7.50 (dd, 1H, J₁ =4.4 Hz, J₂ = 10.0 Hz), 7.75 (dd, 1H, J₁= 2.0 Hz, J₂ = 10.0 Hz), 7.82 (bs, 3H), 8.36 (t, 1H, J =5.6 Hz), 8.39(t, 1H, J = 6.0 Hz), 12.09 # (s, 1H); m/z [M⁺ + 1] 317.1. 103

¹H NMR (DMSO-d₆) δ 2.93 (t, 2H, J = 6.0 Hz), 3.22-3.26 (m, 2H),3.37-3.41 (m, 2H), 3.46 (q, 2H, J = 6.0 Hz), 6.30 (s, 1H), 7.16 (dt, 1H,J₁ = 2.0 Hz, J₂ = 8.8 Hz), 7.49 (dd, 1H, J₁ = 4.4 Hz, J₂ = 8.8 Hz), 7.70(dd, 1H, J₁ =2.0 Hz, J₂ = 10.8 Hz), 7.78 (dd, 1H, J₁ = 5.6 Hz, J₂ = 8.0Hz), 8.21 (d, 1H, J = 8.4 # Hz), 8.29 (t, 1H, J = 5.2 Hz), 8.37 (t, 1H,J = 5.2 Hz), 8.67 (d, 1H, J = 4.4 Hz), 8.72 (s, 1H), 12.06 (s, 1H); m/z[M⁺ + 1] 379.1. 104

¹H NMR (DMSO-d₆) δ 3.09 (t, 2H, J = 7.2 Hz), 3.21-3.26 (m, 2H),3.36-3.39 (m, 2H), 3.55 (q, 2H, J = 7.2 Hz), 6.28 (s, 1H), 7.16 (dt, 1H,J₁ = 2.4 Hz, J₂ = 8.8 Hz), 7.49 (dd, 1H, J₁ = 4.8 Hz, J₂ = 10.2 Hz),7.65 (t, 1H, J =6.4 Hz), 7.69 (s, 1H), 7.72 (s, 1H), 8.21 (t, 1H, J =7.2 Hz), 8.32 (t, 1H, J = 6.0 Hz), 8.37 (t, 1H, J = 4.4 Hz), 8.72 (d,1H, J = # 4.0 Hz), 12.05 (s, 1H); m/z [M⁺ + 1] 379.1. 105

¹H NMR (DMSO-d₆) δ 1.20-1.32 (m, 2H), 1.36-1.43 (m, 2H), 1.88-2.00 (m,4H), 2.50-2.53 (m, 1H), 2.96-3.08 (m, 1H), 3.21-3.28 (m, 2H), 3.46-3.48(m, 2H), 6.31 (s, 1H), 7.16 (dt, 1H, J₁ = 2.4 Hz, J₂ = 9.2 Hz), 7.48(dd, 1H, J₁ = 4.4 Hz, J₂ = 9.2 Hz), 7.73 (dd, 1H, J₁ =2.8 Hz, J₂ = 10.0Hz), 7.82 (bs, 3H), # 8.09(d, 1H, J = 8.0 Hz), 8.39 (t, 1H, J = 5.2 Hz),12.04 (s, 1H); m/z [M⁺ + 1] 371.3. 106

¹H NMR (DMSO-d₆) δ 1.20-1.44 (m, 4H), 1.68-1.76 (m, 2H), 1.81-1.88 (m,1H), 1.96-2.04 (m, 1H), 2.80-2.92 (m, 1H), 3.24-3.30 (m, 2H), 3.44-3.48(m, 2H), 3.72-3.80 (m, 1H), 6.35 (s, 1H), 7.18 (dt, 1H, J₁ = 2.4 Hz, J₂=8.8 Hz), 7.50 (dd, 1H, J₁ = 5.2 Hz, J₂ = 8.8 Hz), 7.79 (dd, 1H, J₁ =2.0 Hz, J₂ = 10.0 # Hz), 7.82 (bs, 3H), 8.17 (d, 1H, J = 8.8 Hz), 8.39(t, 1H, J = 4.8 Hz), 12.09 (s, 1H); m/z [M⁺ + 1]371.2. 107

¹H NMR (DMSO-d₆) δ 3.05-3.08 (m, 2H), 3.14 (t, 4H, J = 4.4 Hz),3.26-3.31 (m, 2H), 3.72 (t, 4H, J = 4.4 Hz), 6.55 (s, 1H), 7.16 (dt, 1H,J₁ = 2.0 Hz, J₂ =10.8 Hz), 7.50 (dd, 1H, J₁ = 5.2 Hz, J₂ = 8.8 Hz), 7.64(dd, 1H, J₁ =2.8 Hz, J₂ = 10.8 Hz), 8.36 (t, 1H, J = 5.2 Hz), 8.83 (bs,2H), 12.04 (s, 1H); m/z [M⁺ + 1]343.1.

Example 10

Compounds of Formula I Exhibit Biological Activity

Compounds of Formula I exhibit inhibitory activity against CDK1, CDK2,CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ, Mek1, CK1, c-Ab1, KDR,IGF-1R, Flt-1, Tek, c-src, FGFR-1 and c-Met kinases. The specificactivity of compounds of Formula I can be determined to inhibit theabove kinases using biological assays known to those of ordinary skillin the art, for example the CDK5 and GSK3β assays described below:

CDK5/p25 Assay

Solutions of test compounds in various concentrations (33 μM to 0.6 nM)were prepared in assay buffer (50 mM MOPS, pH7.2, 5 mM MgCl₂).Recombinant CDK5 (in 5 μl of assay buffer) is added to the wells of a384 well ProxiPlate™. A solution (10 μl) containing 1.5 μM ATP, 1.5 μMof biotinylated CDK5 substrate peptide (LCB-AGAKKAVKKTPKKAKKP), 0.01mCi/ml of [γ-³³P]-ATP in assay buffer is added to the wells. Thereaction is incubated for 60 minutes at room temperature before theaddition of stop solution (10 μl of 50 mM ATP, 5 mM of EDTA, 0.1% TritonX-100 and 5 mg/ml streptavadin-PVT beads in PBS). The plates arecentrifuged for 2 minutes at 2000 rpm and the scintillation signal isquantified using the TopCount (Packard). IC₅₀s are calculated usingXLfit software.

GSK3β Assay

Solutions of test compounds in various concentrations (33 μM to 0.6 nM)were prepared in assay buffer (50 mM MOPS, pH7.2, 5 mM MgCl₂).Recombinant GSK3β (in 5 μl of assay buffer) is added to the wells of a384 well ProxiPlate™. A solution (10 μl) containing 1.5 μM ATP, 1.5 μMof biotinylated CDK5 substrate peptide(biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE) for 60 minutes at roomtemperature before the addition of stop solution (10 μl of 50 mM ATP, 5mM of EDTA, 0.1% Triton X-100 and 5 mg/ml streptavadin-PVT beads inPBS). The plates are centrifuged for 2 minutes at 2000 rpm and thescintillation signal is quantified using the TopCount (Packard). IC₅₀sare calculated using XLfit software. TABLE 2 Percentage Inhibition ofVarious Kinases at 10 μM of Compound

Compound Compound Compound 12 31 33 c-Abl — — — KDR 70 — — Flt-3 — — —IGF-1R — — — PDGFR-β — — 97 c-Kit 86 — — Flt-1 — — — Tek — — 70 c-src 89— 78 CDK1 99 95 97 FGFR-1 89 — — c-Met 74 — —

Compound Compound 24 37 c-Abl 91 86 KDR — — Flt-3 72 75 IGF-1R 82 76PDGFR-β — — c-Kit 79 — Flt-1 85 79 Tek 73 81 c-src 92 90 CDK1 88 98FGFR-1 — — c-Met — —

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and understanding of this applicationand scope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of Formula I:

in which: R¹ and R² are independently selected from hydrogen, halo,cyano, nitro, amino, phenyl, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; or R¹ and R²taken together with the carbon atoms to which R¹ and R² are attachedform a phenyl ring optionally substituted by 1 to 3 substituentsselected from halo, cyano, nitro, amino, methanesulfonyl, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;R³, R⁴ and R⁵ are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;and —X—Y— is selected from —CH(-Z)CH₂—, —C(=Z)-CH₂— and —CZ=CH—; wherein=Z is selected from formula (a) and (b) and -Z is selected from formula(c),(d) and (e):

wherein R⁶, R⁸ and R⁹ are independently selected from hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl andhalo-substituted-C₁₋₆alkoxy; R⁷ is selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,—C(O)OR¹¹ and —C(O)R¹¹; wherein R¹¹ is hydrogen or C₁₋₆alkyl; R¹⁰ isselected from C₁₋₆alkyl, —NR¹¹R¹², C₆₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any alkyl is optionallysubstituted with —NR¹¹R¹¹, C₁₋₆alkoxy or hydroxy; and wherein anycycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionallysubstituted by 1 to 3 substituents selected from halo, hydroxy, cyano,amino, nitro, —C(O)OR¹¹, —C(O)NR¹¹R¹¹, —SNR¹¹R¹¹, —S(O)NR¹¹R¹¹,—S(O)₂NR¹¹R¹¹, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl andhalo-substituted-C₁₋₆alkoxy; wherein R¹¹ is hydrogen or C₁₋₆alkyl; R¹²is C₃₋₁₂cycloalkyl optionally substituted with amino; or R⁹ and R¹⁰together with the nitrogen to which R⁹ and R¹⁰ are attached formC₃₋₁₀heterocycloalkyl; and the pharmaceutically acceptable salts,hydrates, solvates, isomers and prodrugs thereof.
 2. The compound ofclaim 1 of Formula Ia:

in which: R¹ and R² are independently selected from hydrogen and halo;or R¹ and R² taken together with the carbon atoms to which R¹ and R² areattached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo, nitro and amino; R³, R⁴, R⁵, R⁶, R⁸ andR⁹ are independently selected from hydrogen and C₁₋₆alkyl; and R⁷ isselected from hydrogen, C₁₋₆alkyl and —C(O)R¹¹; wherein R¹¹ is hydrogenor C₁₋₆alkyl.
 3. The compound of claim 2 in which R¹ and R² areindependently selected from hydrogen and halo; R³, R⁴, R⁵, R⁶, R⁸ and R⁹are hydrogen; and R⁷ is selected from hydrogen, ethyl and —C(O)CH₃. 4.The compound of claim 3 selected from the group consisting of:4-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;N-[5-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-4-oxo-4,5-dihydro-1H-imidazol-2-yl]-acetamide;2,3-dibromo-4-(2-ethylamino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;and4-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dibromo-6-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one.5. The compound of claim 2 in which R¹ and R² taken together with thecarbon atoms to which R¹ and R² are attached form a phenyl ringoptionally substituted by 1 to 3 substituents selected from halo,methanesulfonyl, nitro and amino; R³, R⁴, R⁶, R⁸ and R⁹ are hydrogen; R⁵is C₁₋₆alkyl; and R⁷ is selected from hydrogen and —C(O)R¹¹; wherein R¹¹is C₁₋₆alkyl.
 6. The compound of claim 5 in which R⁵ is methyl; and R⁷is hydrogen or —C(O)CH₃.
 7. The compound of claim 6 selected from thegroup consisting of:5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-bromo-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-chloro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-fluoro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-9-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-amino-5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-Amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-methanesulfonyl-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;9-amino-5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;N-[5-(7-bromo-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-4-oxo-4,5-dihydro-1H-imidazol-2-yl]-acetamide;and5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-bromo-3-methyl-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.8. The compound of claim 1 of Formula Ib:

in which R¹ and R² are independently selected from hydrogen, halo andphenyl; or R¹ and R² taken together with the carbon atoms to which R¹and R² are attached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo and amino; R³, R⁴ and R⁵ areindependently selected from hydrogen and C₁₋₆alkyl; R⁹ is hydrogen; andR¹⁰ is selected from C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl andC₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any aryl or heteroaryl is optionallysubstituted by 1 to 3 substituents selected from halo, nitro, —C(O)OH,—S(O)₂NH₂, C₁₋₆alkoxy and halo-substituted-C₁₋₆alkyl.
 9. The compound ofclaim 8 in which R¹ and R² are independently selected from halo andphenyl; R³ and R⁴ are hydrogen and R⁵ is methyl; R⁹ is hydrogen; R¹⁰ isselected from C₆₋₁₀aryl-C₀₋₄alkyl and C₅₋₁₀heteroaryl-C₀₋₄alkyl; whereinany aryl or heteroaryl is optionally substituted by halo, nitro, —C(O)OHand halo-substituted-C₁₋₆alkyl.
 10. The compound of claim 9 selectedfrom the group consisting of:2-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoicacid;4-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoicacid;2,3-dibromo-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-[(4-nitro-phenyl)-hydrazono]-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;4-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzenesulfonamide;2,3-dibromo-4-[(7-chloro-quinolin-4-yl)-hydrazono]-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-[(5-trifluoromethyl-pyrimidin-2-yl)-hydrazono]-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-(pyridin-3-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2,3-dibromo-4-(pyridin-4-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;2-phenyl-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;6-methyl-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;and2,3-dichloro-4-(pyridin-2-yl-hydrazono)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one.11. The compound of claim 8 in which R¹ and R² taken together with thecarbon atoms to which R¹ and R² are attached form a phenyl ringoptionally substituted by 1 to 3 substituents selected from halo andamino; R³, R⁴ and R⁵ are independently selected from hydrogen andC₁₋₆alkyl; R⁹ is hydrogen; and R¹⁰ is selected from C₆₋₁₀aryl-C₀₋₄alkyland C₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any aryl or heteroaryl isoptionally substituted by 1 to 3 substituents selected from halo, nitro,—C(O)OH, —S(O)₂NH₂, C₁₋₆alkoxy and halo-substituted-C₁₋₆alkyl.
 12. Thecompound of claim 11 selected from the group consisting of:5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-bromo-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;9-amino-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;4-[N-(7-chloro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-benzenesulfonamide;7-chloro-5-(pyridin-4-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-(pyridin-3-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-fluoro-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-bromo-3-methyl-5-(pyridin-2-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;4-[N′-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-benzenesulfonamide;7-fluoro-5-(pyridin-3-yl-hydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-fluoro-5-[(6-methoxy-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(6-methoxy-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-[(2-chloro-pyridin-3-yl)-hydrazono]-7-fluoro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(2-chloro-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(5-chloro-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-[(5-chloro-pyridin-2-yl)-hydrazono]-7-fluoro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;6-[N′-(7-chloro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-pyridine-3-sulfonicacid amide;6-[N′-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-hydrazino]-pyridine-3-sulfonicacid amide;7-fluoro-5-[(5-trifluoromethyl-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(5-trifluoromethyl-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;7-chloro-5-[(5-nitro-pyridin-2-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;and7-chloro-5-[(6-chloro-pyridin-3-yl)-hydrazono]-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.13. The compound of claim 1 selected from Formula Ic₁ and Ic₂:

in which: R¹ and R² taken together with the carbon atoms to which R¹ andR² are attached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo, cyano, nitro, amino, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;R³, R⁴ and R⁵ are hydrogen; R⁹ is selected from hydrogen and C₁₋₆alkyl;and R¹⁰ is selected from C₁₋₆alkyl, —NR¹¹R¹², C₆₋₁₀aryl-C₀₋₄alkyl andC₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any alkyl is optionally substitutedwith —NR¹¹R¹¹, C₁₋₆alkoxy or hydroxy; and wherein any aryl or heteroarylis optionally substituted by 1 to 3 substituents selected from halo,—C(O)NR¹¹R¹¹ and —S(O)₂NR¹¹R¹¹; wherein R¹¹ is hydrogen or C₁₋₆alkyl;R¹² is C₃₋₁₂cycloalkyl optionally substituted with amino; or R⁹ and R¹⁰together with the nitrogen to which R⁹ and R¹⁰ are attached formC₃₋₁₀heterocycloalkyl.
 14. The compound of claim 13 in which: R¹ and R²taken together with the carbon atoms to which R¹ and R² are attachedform a phenyl ring optionally substituted by 1 to 3 halo substituents;R⁹ is hydrogen or methyl; and R¹⁰ is selected from methyl, ethyl,propyl, pyridinyl, pyridinyl-methyl, 2-amino-ethyl, 2-hydroxyethyl,2-amino-propyl, 2-dimethylamino-ethyl, 2-methoxy-ethyl; and wherein anyheteroaryl is optionally substituted by 1 to 3 substituents selectedfrom halo, —C(O)NH₂ and —S(O)₂NH₂; or R⁹ and R¹⁰ together with thenitrogen to which R⁹ and R¹⁰ are attached form morpholino orpiperazinyl.
 15. The compound of claim 14 selected from the groupconsisting of:2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-pyridin-3-yl-acetamide;2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-pyridin-4-yl-acetamide;4-[2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetylamino]-benzamide;2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(4-sulfamoyl-phenyl)-acetamide;2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(3-sulfamoyl-phenyl)-acetamide;2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-sulfamoyl-phenyl)-acetamide;N-(2-amino-cyclohexyl)-2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(4-amino-cyclohexyl)-2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(4-hydroxy-cyclohexyl)-2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-pyridin-4-ylmethyl-acetamide;N-(2-chloro-pyridin-3-yl)-2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(6-chloro-pyridin-3-yl)-2-(1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(6-chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;N-(2-chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(3-sulfamoyl-phenyl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-4-ylmethyl-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-4-yl-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-propyl-acetamide;N-(2-amino-ethyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(2-hydroxy-ethyl)-acetamide;N-(3-amino-propyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;N-(2-dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(2-methoxy-ethyl)-N-methyl-acetamide;7-fluoro-5-(2-morpholin-4-yl-2-oxo-ethyl)-3,10-dihydro-2H-azepino[3,4-b]indol-1-one;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(2-sulfamoyl-phenyl)-acetamide;7-fluoro-5-(2-oxo-2-piperazin-1-yl-ethyl)-3,10-dihydro-2H-azepino[3,4-b]indol-1-one;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-(4-sulfamoyl-phenyl)-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-2-yl-acetamide;2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-N-pyridin-3-yl-acetamide;4-[2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetylamino]-benzamide;N-(2-Amino-cyclohexyl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide;N-(2-Dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(3-hydroxy-propyl)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-hydroxy-ethyl)-acetamide;N-(2-Amino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-pyridin-3-yl-ethyl)-acetamide;2-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-N-(2-pyridin-2-yl-ethyl)-acetamide;N-(4-Amino-cyclohexyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;N-(2-Amino-cyclohexyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide;and7-Fluoro-5-(2-oxo-2-piperazin-1-yl-ethylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.16. The compound of claim 1 of Formula Id:

in which R¹ and R² are independently halo; or R¹ and R² taken togetherwith the carbon atoms to which R¹ and R² are attached form a phenyl ringoptionally substituted by 1 to 3 substituents selected from halo andnitro; R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; and R⁷ is hydrogen orC₁₋₆alkyl.
 17. The compound of claim 16 selected from the groupconsisting of:2,3-dibromo-4-(2-ethylamino-3H-imidazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one;5-(2-amino-3H-imidazol-4-yl)-7-bromo-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;5-(2-amino-3H-imidazol-4-yl)-7-chloro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one;and5-(2-amino-3H-imidazol-4-yl)-9-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one.18. The compound of claim 1 of Formula Ie:

in which: R¹ and R² taken together with the carbon atoms to which R¹ andR² are attached form a phenyl ring optionally substituted by 1 to 3substituents selected from halo, cyano, nitro, amino, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C¹⁻⁶alkyl and halo-substituted-C₁₋₆alkoxy;R³, R⁴ and R⁵ are hydrogen; R⁹ is selected from hydrogen and C₁₋₆alkyl;and R¹⁰ is selected from C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl andC₅₋₁₀heteroaryl-C₀₋₄alkyl; wherein any alkyl is optionally substitutedwith —NR¹¹R¹¹, C₁₋₆alkoxy or hydroxy; and wherein any aryl or heteroarylis optionally substituted by 1 to 3 substituents selected from halo,—C(O)NR¹¹R¹¹ and —S(O)₂NR¹¹R¹¹; wherein R¹¹ is hydrogen or C₁₋₆alkyl; orR⁹ and R¹⁰ together with the nitrogen to which R⁹ and R¹⁰ are attachedform C₃₋₁₀heterocycloalkyl.
 19. The compound of claim 18 in which: R¹and R² taken together with the carbon atoms to which R¹ and R² areattached form a phenyl ring optionally substituted by 1 to 3 halosubstituents; R⁹ is hydrogen or methyl; and R¹⁰ is selected from methyl,ethyl, propyl, pyridinyl, pyridinyl-methyl, 2-amino-ethyl,2-hydroxyethyl, 2-amino-propyl, 2-dimethylamino-ethyl, 2-methoxy-ethyl;and wherein any heteroaryl is optionally substituted by 1 to 3substituents selected from halo, —C(O)NH₂ and —S(O)₂NH₂; or R⁹ and R¹⁰together with the nitrogen to which R⁹ and R¹⁰ are attached formmorpholino or piperazinyl.
 20. The compound of claim 19 selected fromthe group consisting of:1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-3-yl-urea;4-[3-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-ureido]-benzenesulfonamide;3-[3-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-ureido]-benzenesulfonamide;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-propyl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-4-yl-urea;1-(2-Chloro-pyridin-4-yl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-2-yl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-isoxazol-3-yl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-thiazol-2-yl-urea;1-(4-Amino-cyclohexyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(3-hydroxy-propyl)-urea;1-(2-Dimethylamino-ethyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(2-hydroxy-ethyl)-urea;1-(2-Amino-ethyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-pyridin-4-ylmethyl-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(2-pyridin-3-yl-ethyl)-urea;1-(7-Fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-3-(2-pyridin-2-yl-ethyl)-urea;and1-(2-Amino-cyclohexyl)-3-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidenemethyl)-urea.21. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in combination with a pharmaceuticallyacceptable excipient.
 22. A method for treating a disease in an animal,wherein the disease is mediated by a cell signaling pathway thatcomprises CDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit, PDGFRβ,Mek1, CK1, c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1 and/or c-Met,which method comprises administering to a animal in need of suchtreatment a therapeutically effective amount of a compound of claim 1.23. The use of a compound of claim 1 in the manufacture of a medicamentfor treating a disease in an animal, wherein a cell signaling pathwaythat comprises CDK1, CDK2, CDK4, CDK5, GSK3β, Bcr-ab1, Flt-3, c-Kit,PDGFRβ, Mek1, CK1, c-Ab1, KDR, IGF-1R, Flt-1, Tek, c-src, FGFR-1 and/orc-Met contributes to the pathology and/or symptomology of the diseaseand the compound alters the cell signaling pathway.